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a g e n ts i n l ess heav il y p r e tr ea te d p atie n ts a nd i n t h e u se o f d i f fere n t do se sc h e du l es f o r o t he r he m a t o l og ic mali gn a n cies . Mec h a n i s m o f Ac ti on Cl of a r a b i ne i s i nac ti ve i n it s p are n t f o rm a nd, li k e o t h er pu ri n e a n al og s , it r e qu i r es i n tr ace ll u l a r ac ti va ti on by d CK t o f o rm t h e m onopho s ph ate nu cle o ti de, wh i ch unde r goes fu rt h er meta bo lism t o t h e c y t o t ox ic t r i pho s pha t e m e t abo lit e. C l o f a ra b i n e tri pho s ph ate is t h e n i n c o r po rate d i nto DNA, resu lti ng i n cha i n t e rmi n ati on, a nd i nh i b iti on o f DNA s yn t h esis a nd fun cti on o r t he tri phospha t e f o rm ca n d irectl y i nh i b it DNA po l y merases α , β, a nd γ , wh i ch i n t u r n, i n t e rf e res wit h DNA c h ai n el ong ati on, DNA s yn t h esi s, and DNA r epa i r . T h e tri pho s ph ate meta bo lite is als o a po te n t i nh i b it or o f ri bonuc l eo ti de r e d u ctase , f u rt h er me d iati ng t h e i nh i b iti on o f DNA b i osyn t hes i s by r educ i ng t h e le v els o f k e y d e oxy ri bonu cle o ti d e pools. Mec h a n i s m s o f Res i s t ance Se v e r al r es i s t ance m echan i s ms h a v e b ee n i d e n tifie d i n v ari ou s p recli n ica l s y stems, and t hey i nc l ude de crease d acti v ati on o f t h e d r ug t h r ough t h e r e du ce d exp r ess i on o f t he anabo lic e n z y me d e oxy c y ti d i n e k i n ase , t h e d ec r eas ed tr anspo rt o f d r ug int o cells v ia t h e nu cle o si d e tra n s po rter p r o t ein, a nd t h e inc r eased exp r ess i on o f CTP s yn t h etase acti v it y res u lti ng i n i n c r ease d concen tr a ti ons o f co m p eti ng phy si o l og ic nu cle o ti d e s ub strate d C T P . T o da t e, t he p r ec i se r es ista n ce mec h a n ism(s) t h at are rele v a n t i n t he cli n ical se tti ng r e m a i n t o be d etermi n e d. Cli n ical P ha rm aco l ogy Approx i ma t e l y 50 % t o 60 % o f a n a d mi n istere d do se o f d r ug is e x crete d un c h a nged i n t he u ri ne, and the termi n al h alf-life is on t h e o r d er o f 5 hou r s. T o d ate , t he pa t hways f o r non re n al elimi n ati on h a v e no t b ee n well d efi ned. Ca u ti on shou l d be exe r c i sed i n p atie n ts wit h a bno rmal re n al f un cti on, a nd c on c o m i t an t use o f m ed i ca ti on s kno w n t o ca u se re n al t ox icit y s hou l d b e a vo i d e d du ri ng d r ug tr ea tm en t . T ox icit y

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8. O ’ Conno r OA. Pr a l a tr ex ate: a n eme r g i ng n ew a g e n t wit h acti v it y i n T - cell l y m pho m as. Cu rr Op i n O n c o l 2006 ; 18 : 591–597. 9. Berti no JR, Göke r E , Go rlic k R , et al . Resista n ce mec h a n isms t o met ho t rexa t e i n t u m o r s. Onco l og ist 1996 ; 1 : 223–226. 10. Zhao R, Go l d m an I D. Resista n ce t o a n tif o lates . O n c og e n e 2003 ; 22 : 7431–7457. 1 1. G r e m J L . 5 -Fl uo r ou r ac il: f o rt y - p l u s a nd still tic k i ng. A re v iew o f its pr ecli n i ca l and c li n i ca l deve l op me n t . I nv est New Dr ug s 2000 ; 18 : 299–313. 12. Saif M W , E zze l d i n H, V a n ce K , et al . DPYD *2 A m u tati on : t h e m ost c o mm on m u t a ti on assoc i a t ed wit h DPD d eficie n c y . Ca n cer C h em o t h er P h a r ma co l 2007 ; 60 : 503–507. 13. G r e m J L . B i oche mi ca l m odu lati on o f 5 -FU i n s y stemic treatme n t o f a dv a n ce d co l o r ec t a l cance r . O n c o l ogy ( W illist on Par k ) 2001 ; 15 : 13–19. 14. Saif M W , S hah MM, S h a h AR . Fl uo r opy rimi d i n e-ass o ciate d ca rd i o t ox i c it y : r ev i s it ed. E xp ert O p i n Dr ug Saf 2009 ; 8 : 191–202. 15. Saif M W , El oube i d i MA, R u ss o S , et al . P h ase I st udy o f ca p ecita b i ne w it h conco mit an t ra d i o t h era py f o r p atie n ts wit h l o call y a dv a n ce d panc r ea ti c cance r: e xp ressi on a n al y sis o f g e n es relate d t o ou tc o m e. J C li n Onco l 2005 ; 23 : 8679–8687. 16. Geye r C E , F o r s t e r J, Lin dqu ist D , et al . La p ati n i b p l u s ca p ecita b i ne for HER2 - pos iti ve advanced breast ca n ce r . N E ng l J Me d 2006 ; 355 : 273 3 – 2743. 17. Saif M W , Ka tirt zog l ou NA , S y ri go s KN . Ca p ecita b i n e: a n ov er v ie w of t h e si de e f f ec t s and t he ir ma n a g eme n t . A n tica n cer Dr ug s 2008 ; 19 : 44 7 – 464. 18. V an Cus t e m E , V e r s l yp e C , T ej p ar S . Oral ca p ecita b i n e: b ri dg i ng t he A tla n tic d i v i de i n co l on canc er treatme n t . Semi n O n c o l 2005 ; 32 : 43–51.

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29. Saif M W , S e ll e r s S , Li M , et al . A ph ase I st udy o f b i-wee k l y a d mi n is t r a ti on o f 24 - h ge m c i t a b i n e f o ll o we d by 24 - h iri no teca n i n p atie nts w it h s o li d t u m o r s. Cance r Ch em o t h er P h armac o l 2007 ; 60 : 871–882. 30. Be r g m an AM, Pi nedo HM , Peters GJ . Determi n a n ts o f resista n ce to 2 ′ , 2 ′ -d ifl uo r odeoxycy ti d i ne ( g emcita b i n e) . Dr ug Resist U pd ate 2002 ; 5 :1 9– 33. 31. Saif M W , L ee Y , K im R . Har n essi ng g emcita b i n e meta bo lism: a st ep t ow a rd s pe r sona li zed m ed i c i n e f o r p a n creatic ca n ce r . T h er A dv Me d O ncol 2012 ; 4 : 341–346. 32. Hong S P , W en J, Bang S , et al . CD 44 - po siti v e cells are res pon si b l e for g emcit ab i ne r es i s t ance i n p a n creatic ca n cer cells . I n t J Ca n cer 2009 ; 125 : 2323–2331. 33. Po p li n E , F eng Y , Be rli n J , et al . P h ase III , ra ndo mize d st udy o f g emcitabi ne and oxa li p l a ti n v ers u s g emcita b i n e (fi x e d - do se rate i n f u si o n) c o m p a red w it h ge m c it ab i ne ( 30 -mi nu te i n f u si on ) i n p atie n ts wit h p a n c r eati c ca r c i no m a E 6201 : a trial o f t h e Easter n C oop erati v e O n c o l ogy Group. J C li n Onco l 2009 ; 27 : 3778–3785. 34. Hande KR. P u ri ne an timeta bo lites . I n : C h a bn er BA , L ongo DL , e ds. Ca n ce r Che m o t he r apy and B i o t h era py : Pri n ci p les a nd Practic e , 4 t h e d. P h ila d el ph i a : Li pp i nco tt –Rav e n ; 2006 : 212. 35. Evans W E . P ha rm acogen etics o f t h i opu ri n e S-met hy ltra n sferase a nd t h i opur i ne t he r ap y . T he r D r u g M on it o r 2004 ; 26 : 186–191. 36. W ang L , W e i nsh il bou m R . T h i opu ri n e S-met hy ltra n sferase ph a r ma cogene ti cs : i ns i gh t s, ch alle ng es , a nd f u t u re d irecti on s . O n c og e n e 2006 ; 25 : 1629–1638. 37. V o r a A, M it che ll CD, Le nn ar d L , et al . T ox icit y a nd e f ficac y o f 6 -t h i ogu a n i ne ve r sus 6 -m e r cap t opu ri n e i n c h il dhood l y m phob lastic le uk ae m i a : a r ando mi sed tri a l . La n cet 2006 ; 368 : 1339–1348.

20 T opo i so m e r ase I n t e r ac ti v e A g e n ts

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20 T opo i so m e r ase I n t e r ac ti v e A g e n ts

20 T opo i so m e r ase I n t e r ac ti v e A g e n ts

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Kh a nh T . Do, S h i vaan i Ku m m a r , James H . D o r o s ho w , a nd Y v es P o mmi e r C LA SSIFI C A TI ON, B I OCH EMICAL , AND BIOLOGIC FUNCTION S O F T O P O IS OM E RA SES Nu cleic ac i ds ( DNA and RN A) b ei ng l ong po l y mers , t opo is o merases f ul f ill t h e n eed f o r ce ll u l a r DNA t o b e d e n sel y p ac k a g e d i n t h e cell nu cle u s , t r a n sc r i bed, r ep li ca t ed, and ev e n l y d istri bu te d b etwee n d a ugh ter cells fo ll ow i ng r ep li ca ti on w it hou t ta ng les . T opo is o merases are ub i qu it ou s a nd esse n tia l f o r a ll o r gan i s m s as t h e y p re v e n t a nd res o l v e DNA a nd RNA e n ta ng l e m en t s and r eso l ve D NA s up erc o ili ng du ri ng tra n scri p ti on a nd r e p licati on. T h i s chap t e r fir s t su mmarizes t h e b asic eleme n ts n ecessar y t o und e r sta nd t he m echan i s m o f acti on o f t opo is o merases a nd t h eir i nh i b it o r s. M or e de t a il ed i n f o rm a ti on ca n b e f ound i n rece n t re v iew s – a nd tw o r ece n t b o oks. T he second part o f t h e c h a p ter s u mmarizes t h e u se o f t opo is o m e r ase i nh i b it o r s as an tica n cer d r ug s . Classi f i ca ti on o f T opo i so m e r a ses Hu ma n ce ll s con t a i n s i x t opoi s o merase g e n es , w h ic h h a v e b ee n numbe r ed h i s t o ri ca ll y . T h e c o mm on l y u se d a bb re v iati on s are T op1 f o r t opo is o m e r ases I ( T op1 mt be i ng t h e mit o c hond rial t opo is o merase w ho s e g e n e is encoded i n t he ce ll nuc le u s) T op2 f o r t opo is o merases II , a nd T op3 for t opo i so m e r ases III . T op1 was t h e first e uk ar yo tic t opo is o meras e d isc ov er ed by Cha m poux an d D u l b ecc o . T opo is o merases s o l v e DNA t opo l og ic p r ob l e m s by cu tti ng t h e DNA b ac kbon e a nd reli g ati ng wit hout t h e assi s t ance o f any add iti ona l li g ase . T op1 a nd T op3 act by clea v i n g/r e li ga ti ng a s i ng l e s tra nd o f t h e DNA dup le x, w h ereas T op2 e n z y mes c l eave and r e li ga t e bo t h stra nd s , ma k i ng a f ou r –b ase p air r e v e r si b l e s t agge r ed cu t ( ) . It is c onv e n ie n t t o remem b er t h at odd - nu m b e red t opo i so m e r ases ( T op1 a nd T op3 ) clea v e a nd reli g ate on e stra nd, wh e r eas t he even nu m be r ed t opo is o merases ( T op2 s) clea v e a nd reli g ate bo t h st rands.

20 T opo i so m e r ase I n t e r ac ti v e A g e n ts

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Bi o c h emi ca l Cha r ac t e ri s ti cs a nd Clea v a g e C o m p le x es o f t h e Di f fere n t T opo is ome r ases Th e DNA cu tti ng /r e l ega ti on m ec h a n ism is c o mm on t o all t opo is o meras es a nd u tili zes an enzy m e ca t a l y tic t y r o si n e resi du e acti ng as a nu cle oph ile a nd b ec o mi ng cova l en tl y a tt ach e d t o t h e e nd o f t h e b r ok e n DNA . T h ese

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a nd T op1 mt a r e t he s im p l es t , n ic k i ng /cl o si ng, a nd rela x i ng DNA as m ono m e r s i n t he absence o f co fact o r , a nd e v e n at ice tem p erat u re . T op2 e n z y mes , on t he o t he r hand, are t h e m o st c o m p le x t opo is o merases w o r king as d imer s, r equ iri ng A TP b i nd i ng a nd hyd r o l y sis , a nd a d i v ale n t metal ( M g 2+ ) fo r ca t a l ys i s. T op3 enzy mes als o re qu ire M g 2+ f o r catal y sis bu t fun cti on as m ono m e r s w it hou t A TP re qu ireme n t . N o ta b l y , t h e DNA s ub st r at es d i f f e r f o r T op3 enzy mes . W h ereas bo t h T op1 a nd T op2 p r o ce ss doub le -s tr anded DNA, t he T op3 s ub strates n ee d t o b e si ng le-stra nd e d nu cleic a c i ds ( DNA f o r T op3α a nd DNA o r RNA f o r T op3 β) . D i f f e r e n ti a l T opo i so m e ri za ti on Mec h a n isms: Swi v eli ng V ers u s Stra nd Passa g e , DNA V e r sus RNA T opo is o merases T opo is ome r ases use t wo m a in mec h a n isms t o c h a ng e nu cleic t opo l og y . The f i r st is by “un t w i s ti ng” t he D NA dup le x. T h is mec h a n ism is un i qu e t o T op1, wh i ch, by an enzy m e - a ss o ciate d si ng le-stra nd b rea k, all o ws t h e brok e n s tr and t o r o t a t e a r oun d t h e i n tact stra nd (see un til D NA s up e r c oi li ng i s d i ss i pa t ed. A t t h is po i n t , t h e stac k i ng e n er gy o f a d jace n t DNA b a ses r ea li gns t he b r ok e n e nd s , a nd t h e 5 ′- hyd r oxy l e nd attac k s t h e 3′ - pho s ph ot y r osy l end, t he r eby rele g ati ng t h e DNA . A remar k a b le feat u re o f

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t h is T op1 un t w i s ti ng m echan i s m is its e x treme efficie n c y wit h a r o tati on s p ee d a round 6,000 r p m and relati v e i nd e p e nd e n ce fr o m t o r qu e , t h ere by all ow i ng f u ll r e l axa ti on o f D NA s up erc o ili ng . Th e sec ond t opo l og i c m echan ism is by “stra nd p assa g e . ” T h is mec h a n ism all ow s th e passage o f a doub le- o r a si ng le-stra nd e d DNA ( o r RNA) t hrough t he c l eavage co m p l ex es . T op2α a nd T op2 β bo t h act by all o wi ng the p assa g e o f an i n t ac t DNA du ple x t h r ough t h e DNA doub le-stra nd b rea k g e n e r ate d by t he enzy m es. Af ter w h ic h, T op2 reli g ates t h e b r ok e n dup le x. S u c h r e ac ti ons pe rmit DNA d ecate n ati on, unkno tti ng, a nd rela x ati on o f s up e r c oi l s T op3 enzy m es a l so act by stra nd p assa g e bu t on l y p ass on e nu cleic a c i d s tr and t h r ough t h e si ng le-stra nd b rea k g e n erate d by t h e e n z y mes . I n t he case o f T op3α, t h e s ub strate is a si ng le-stra nd e d DNA se g me n t ( such as a doub l e - Ho lli d a y j un cti on ) , w h ereas i n t h e case o f T op3β, th e subs tr a t e can be a s i ng le-stra nd e d RNA se g me n t , wit h T op3 β acti ng as a RNA t opo i so m e r a se . T O P OISOM E RA SE I NH I B I T ORS AS INTER F ACIAL POISONS T opo is ome r ase I nh i b it o r s Ac t as I n terfacial I nh i b it o rs by Bi nd i ng at t h e T opo is ome r ase–DNA I n t e rf a ce a nd T ra pp i ng T opo is o merase Clea v a g e C o m p le xes Rele g ati on o f t he c l eavage co m p le x es is d e p e nd e n t on t h e str u ct u re o f t he e nd s of t he b r oken DNA (i .e., t h e reali gn me n t o f t h e b r ok e n e nd s) . Bi nding t h e drugs a t t he enzy m e–DNA i n terface misali gn s t h e e nd s o f t h e DNA and pr ecl udes r e l ega ti on, r esu lti ng i n t h e sta b ilizati on o f t h e t opo is o merase clea v a ge co m p l exes ( T op1cc a nd T op2 cc) . Cr y stal str u ct u res o f d r ug - bound clea v a ge co m p l exes have fir m l y esta b lis h e d t h is mec h a n ism f o r bo t h T op1 -a nd T op2 -t a r ge t ed d r ugs. I t is c r it ica l t o unde r s t and t hat t h e c y t o t ox ic mec h a n ism o f t opo is o merase i nh i b it ors r equ ir es t he d r ugs t o tra p t h e t opo is o merase clea v a g e c o m p le xes r at h e r th an b l ock ca t a l y ti c ac t iv it y . T h is sets a p art t opo is o merase i nh i b it o r s fro m cla ss i ca l enzy m e i nh i b it o rs s u c h as a n tif o lates . I nd ee d, kno c k i ng out T op1 r e nde r s yeas t ce ll s t o t a ll y imm un e t o cam p t o t h eci n , a nd re du c ing e n z y me l eve l s i n cance r ce ll s c on fers d r ug resista n ce . C onv ersel y , i n b rea st

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ca n ce r s , a m p lifi ca ti on o f T OP2 A , w h ic h is on t h e same l o c u s as HER 2, c on t r i butes t o t he e f fi cacy o f doxo r ub ici n Als o, cell u lar m u tati on s o f T op1 a nd T op2 t ha t r ende r s c ells i n se n siti v e t o t h e tra pp i ng o f t opo is o m e r ase c l eavage co m p le x es p r odu ce h i gh resista n ce t o T op1 o r T op2 i nh i b it o r s. Based on t h is tra pp i ng o f clea v a g e c o m p le x es mec h a n is m, w e r e f e r t o t opo i so m e r ase i nh i b it o rs as t opo is o merase clea v a g e c o m p le x -ta r g ete d d r ugs. T op1 cc - T a r ge t ed D r ugs ( Camp t o t h eci n a nd N on cam p t o t h eci n Deri v ati v e s ) K ill Can ce r Ce ll s by Rep li ca ti on C o llisi on s T op1 cc ar e cy t o t ox i c by t he ir c onv ersi on i n t o DNA d ama g e by re p licati on a nd t r a nsc ri p ti on f o r k co lli s i o ns . T h is e xp lai n s w hy c y t o t ox icit y is d irec tly r elate d t o d r ug exposu r e and w hy arresti ng DNA re p licati on p r o tects cel ls fro m cam p t o t hec i n . T he co llisi on s arise fr o m t h e fact t h at t h e d r ug s , by sl ow i ng down t he n i ck i ng / c l o si ng acti v it y o f T op1, un c oup le t h e k i n etics o f T op1 w it h t he po l y m e r ases and h elicases , w h ic h lea d po l y merases t o c o lli d e i n t o T op1cc ( . S u c h c o llisi on s h a v e tw o c on se qu e n ce s. Th e y g e ne r a t e doub l e - s tr and b rea k s (re p licati on a nd tra n scri p ti on r uno f f) a nd i rr e ve r s i b l e T op1–DNA addu cts (see ) . T h e re p licati on doub le -s tr and b r eaks a r e r epai re d by ho m o l ogou s rec o m b i n ati on, w h ic h e xp lai n s t he hype r sens iti v it y of BRCA- d eficie n t ca n cer cells t o T op1 cc-ta r g ete d d r ugs T he T op1 - cov ale n t c o m p le x es ca n b e rem ov e d by tw o p at hw ay s, t he exc i s i on pa t hway ce n tere d ar ound t y r o s y l-DNA- pho s ph o d i es t e r ase 1 (T D P 1 ) a nd t h e e ndonu clease p at h wa y i nvo l v i ng 3′ - f la p e ndonuc l eases such as XP F-ERCC 1 . It is als o po ssi b le t h at d r ug -t r a pp e d T op1cc d ir ec tl y gene rate DNA doub le-stra nd b rea k s w h e n t h e y a r e w it h i n 10 base pa ir s on oppo site stra nd s o f t h e DNA dup le x o r w h e n t h e y o cc ur nex t t o a p r eex i s ti ng s i ng le-stra nd b rea k on t h e oppo site stra nd. Fi n all y , it i s no t exc l uded t ha t t opo l og ic d efects c on tri bu te t o t h e c y t o t ox i c it y o f T op1cc -t a r ge te d d r ug s (t h e acc u m u lati on o f s up erc o il s

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C y t o t ox i c Mechan i s m s o f T op2 cc- T a r g ete d Dr ug s (I n tercalat o rs a nd D emet hy l E p i podophy ll o t ox i n s) C on t r a ry t o ca m p t o t hec i ns, T op2 i nh i b it o rs k ill ca n cer cells wit hou t r e qu i r i ng DNA r ep li ca ti on f o r k c o llisi on s . I nd ee d, e v e n after a 30 -mi nu te e xpo s ure, doxo r ub i c i n and o t h er T op2 cc-ta r g ete d d r ug s ca n k ill ov er 99% of t h e c e ll s, wh i ch i s i n vas t ex cess o f t h e fracti on o f S- ph ase cells i n tis sue c u lt ur e ( gene r a ll y l ess t han 5 0%) T h e c o llisi on mec h a n ism i n t h e c ase of T op2cc -t a r ge t ed d r ugs ( se e a pp ears t o i nvo l v e tra n scri p ti on a nd pro te o l ys i s o f bo t h T op2 a nd RNA po l y merase II S u c h sit u ati on wou l d t hen l ead t o DNA dou ble-stra nd b rea k s by d isr up ti on o f t h e T op2 d ime r i n t e rf ace ( see . Alter n ati v el y , t h e T op2 ho m od imer i n te rf ac e cou l d be d i s j o i ned by mec h a n ical te n si on (see . Y et , it is im por t an t t o bea r i n mi nd t h at 90 % o f T op2 cc tra pp e d by et opo si d e are no t c once rt ed and, t he r e f o r e, con sist i n si ng le-stra nd b rea k s , w h ic h is d i f f e r e n t fr o m doxo r ub i c i n, w h ic h tra p s bo t h T op2 m ono mers a nd p r oduces a maj or i ty o f DNA doub l e - s t r a nd b rea k s . Fi n all y , it is no t e x cl ud e d t h a t t opo l og ic de f ec t s r esu lti ng fr o m T op2 se qu estrati on by t h e d r ug -i ndu ce d clea v a ge co m p l exes cou l d con tri bu te t o t h e c y t o t ox icit y o f T op2 cc-ta r g et ed drug s ( se e . S uch topo l og ic d efects w ou l d i n cl ud e p ersiste n t DNA k n o t s and ca t enanes, po te n tiall y lea d i ng t o c h r o m o s o me b rea k s dur i ng mit os i s. T O P OISOM E RA SE I I NH I BI T ORS: CAMP T OTHECINS AND B EYOND Cam p t othec i n i s an a l ka l o i d ide n tifie d i n t h e 1960 s by W all a nd W a n in a sc r ee n o f p l an t ex tr ac t s f o r ant i n e op lastic d r ug s . T h e tw o water-s o l ub le d e r i v ati ves o f ca m p t o t hec i n con tai n i ng t h e acti v e lact on e f o rm are t opo tec an and iri no t ecan, wh ic h are a pp r ov e d by t h e U . S . F ood a nd Dr u g Ad mi n istr a ti on (F DA ) f o r t he treatme n t o f se v eral ca n cers . I n a dd iti on, se v e r al T op1cc -t a r ge ti ng d r ug s are i n cli n ical d e v el op me n t , i n cl ud i ng cam p t o t hec i n de ri va ti ves and f o rm u lati on s (i n cl ud i ng h i gh– m o lec u la r - w ei gh t con j uga t es o r li poso mal f o rm u lati on s) , as well as non cam p t o t h e cin c o m pounds t ha t exh i b it g r ea ter po te n c y o r non cr o ss resista n ce t o iri no te can a nd t opo t ecan i n p r ec li n i ca l c a n cer m od els .

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Ir i no teca n Ir i no teca n, a p r od r ug con t a i n i ng a bu l ky d i p i p eri d i n e si d e c h ai n at C- 10 ( ) , i s c l eaved by a ca r boxy lesterase-c onv erti ng e n z y me i n t h e li ve r a nd o t he r ti ssues t o gene r a t e t h e acti v e meta bo lite , SN- 38. Iri no teca n is F DA a pp r oved f o r t he tr ea tm en t o f c o l o rectal ca n cer i n t h e metastatic setti ng a s fir s t-li ne tr ea tm en t i n c o m b i n ati on wit h 5 -fl uo r ou racil/le u c ovo r in (5-FU / L V ) and as a s i ng l e ag e n t i n t h e sec ond -li n e treatme n t o f p r og ress ive c o l or ectal cance r a ft e r 5 -F U–b ase d t h era py (see Newe r t h e r a p euti c uses o f iri no t ecan i n cl ud e a c o m b i n ati on wit h ox ali p lati n a n d 5 -F U as f ir s t-li ne tr ea tm en t i n p a n creatic ca n ce r Iri no teca n is a dd iti on al ly u se d i n c o m b i na ti on w it h c i sp lati n o r car bop lati n i n e x te n si v e-sta g e sma ll -cell l ung cance r as we ll as refract o r y es oph a g eal a nd g astr o es oph a geal j un cti on ( G E J ) cance r s, gas tr i c ca n ce r , cer v ical ca n ce r , a n a p lastic g li o ma s a nd g li ob l as t o m as, and non–sm all-cell l ung ca n cer ( ) . Iri no te can is u s u all y ad mi n i s t e r ed i n tr av e nou sl y at a do se o f 125 m g / m 2 f o r 4 wee ks w it h a 2 - week r es t pe ri od i n co m b i n ati on wit h bo l u s 5 -FU/ L V , 180 m g /m 2 e v e ry 2 weeks i n co m b i na ti on wit h a n i n f u si on o f 5 -FU/ L V , o r 350 m g / m 2 e v e ry 3 weeks as a s i ng l e agen t . D ia rrh e a and m ye l osupp r ess i on are t h e m o st c o mm on t ox icities ass o ciate d w it h i r i no t ecan ad mi n i s tr a ti o n . T w o mec h a n isms e xp lai n iri no teca n -i ndu ce d d i a rr hea. Acu t e cho li n e r g ic e f fects res u lti ng i n a bdo mi n al c r am p i ng and d i a rr hea occu r wit h i n 24 hou rs o f d r ug a d mi n istrati on are the r es u lt of ace t y l cho li nes t e r ase i nh i b iti on by t h e p r od r ug, a nd ca n b e treat ed w it h t h e ad mi n i s tr a ti on o f a tro p i n e . Direct m u c o sal c y t o t ox icit y wit h d ia rrh ea i s t yp i ca ll y obse r ved after 24 hou rs a nd ca n res u lt i n si gn ifica n t m orb i d it y . S y m p t o m s a r e m a na g e d wit h l op erami d e . He p atic meta bo lis m a nd b ili a r y exc r e ti on accoun ts f o r >70 % o f t h e elimi n ati on o f t h e a d mi n is te r ed dose, w it h r ena l e x creti on acc oun ti ng f o r t h e remai nd er o f the do se . SN- 38 i s g l ucu r on i da t e d i n t h e li v er by UGT 1 A 1, a nd d eficie n cies in t h is p at hway i nc r ease t he ri sk o f d iarr h ea a nd m y el o s upp ressi on. D o se r e du cti ons a r e r eco mm ended f o r p atie n ts w ho are ho m o z ygou s f o r t h e

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n t h at t h e add iti on o f a bu l ky c o n j ug ate w ou l d all o w f o r a m o re c on siste n t d eli v e ry sys t e m and ex t end t h e h alf-life o f t h e m o lec u le . CR LX1 0 1, f o rm e rl y I T - 101, a c ov ale n t c y cl od e x tri n - po l y et hy le n e g l y c o l c opo l y m e r ca m p t o t hec i n conjug ate , h as p lasma c on ce n trati on s a nd area und e r t he cu r ve ( AUC ) t ha t a re a pp r ox imatel y 100 -f o l d h i gh er t h a n cam p t o t hec i n, w it h a ha lf-lif e i n t h e ra ng e o f 17 t o 20 hou rs c o m p are d t o 1.3 hour s f o r ca m p t o t hec i n It h as d em on strate d a n tit u m o r acti v it y i n pr ecli n i ca l s t ud i es i n iri no t ec a n -resista n t t u m o rs wit h c o m p lete t u m o r r e gr essi on i n hu m an non–s mall-cell l ung ca n ce r , Ewi ng sarc o ma , a nd l y m pho m a xenog r a ft m ode l s . Prelimi n ar y d ata fr o m P h ase 1 st ud ies i nd icate t ha t CR L X101 i s we ll t o lerate d at a do se o f 15 m g / m 2 a d mi n is te r ed i n a b i week l y ad mi n istrati on sc h e du le . It is c u rre n tl y b ein g st ud ie d in P hase 2 s t ud i es as a si ng le a g e n t a nd i n c o m b i n ati on wit h c h em o t he r apeu ti c agen t s i n l ung, re n al cell ca n ce r , a nd gyn ec o l og ic mali gn a nc i es . – E ti r i no t ecan pego l ( NK T R - 102 ) , a n iri no teca n po l y mer c on j ug ate , h as a l ong e r p l as m a c ir cu l a ti on time wit h a l o wer ma x im u m c on ce n trati on o f SN - 38 c o m pa r ed w it h iri no t ecan. It was e v al u ate d i n a P h ase 2 st udy i n p lati nu m-r es i s t an t r e fr ac t o r y ep it h elial ov aria n ca n cer at a do se o f 145 m g /m 2 ad mi n i s t e r ed on a sch e du le o f e v er y 21 d a y s; a me d ia n p r og ressi on - fr ee s urv i va l o f 5.3 m on t hs a n d me d ia n ov erall s u r v i v al o f 1 1.7 m on t h s w as ob se rv e d T wo schedu l es o f a d mi n istrati on, 145 m g / m 2 a d mi n istere d e v e ry 14 days ve r sus eve r y 21 d a y s , h a v e b ee n teste d i n a P h ase 2 st udy o f NKT R -102 i n pa ti en t s w it h pr e v i ou sl y treate d metastatic b reast ca n ce r

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s o li d t u m o r s. A P hase 3 tri a l (T h e BEACON St udy ) is und erwa y e v al u a ting NKT R -102 aga i ns t t he phys i c ia n s’ c ho ice i n refract o r y b reast ca n ce r . A s a n alt e r na ti ve t o m ac r o m o lec u lar c on j ug ates , attem p ts h a v e als o b ee n ma d e t o a lt e r t he ca m p t o t hec i n p e n tac y clic ri ng str u ct u re wit h m od i f ic a ti ons o f t he A and B ri ng (see ) i n a n e f f o rt t o im p r ove s o l ub ilit y and enhance an tit u m o r acti v it y . Str u ct u re – acti v it y relati on s h i p st ud ies have shown t ha t subs tit u ti on s at t h e 7, 9, a nd 10 po siti on s ser v e to e nh a n ce t he an tit u m o r ac ti v it y o f cam p t o t h eci n . Bel o teca n, a nov el cam p t o t hec i n ana l og, has a w ate r -s o l ub ilizi ng g r oup at t h e 7 po siti on o f the B r i ng o f ca m p t o t hec i n ( see ) . Se v eral P h ase 2 st ud ies h a v e e v al u ate d be l o t ecan i n co m b i n ati on wit h car bop lati n i n rec u rre n t ov aria n ca n ce and i n co m b i na ti on w it h cis p lati n i n e x te n si v e-sta g e small-cell l ung ca nce r , de m ons tr a ti ng acti v it y i n t h ese ca n cers; ho we v e r , t h ese c o m b i na ti ons we r e assoc i a t e d wit h p r o mi n e n t h emat o l og ic t ox icities . P hase 2 st ud ies eva l ua ti ng be l o t ecan as a si ng le a g e n t i n p atie n ts wit h rec u rre n t o r progr es s i ve ca r c i no m a o f t he uteri n e cer v i x faile d t o s ho w acti v it y

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G imatec an i s a li poph ili c o r a l cam p t o t h eci n a n al og (see . P h a r ma cok i ne ti c s t ud i es de m on strate t h at g imateca n is p rimaril y p rese nt in p lasma as t he l ac t one f o rm ( > 8 5 %) , a nd h as a l ong h alf-life o f 77.1 + / − 29.6 hou r s, w it h an i nc r ease i n ma x im u m c on ce n trati on (Cma x ) a nd AUC of t hr ee- t o s i x -f o l d a ft e r m u lti p le do si ng . P h ase 2 st ud ies s ho w t h at g imateca n has de m ons tr a t ed acti v it y i n p re v i ou sl y treate d ov aria n ca n ce r , w it h m ye l osupp r ess i on as t he mai n t ox icit y . N e w e r deve l op m en t o f ana l og s h a v e attem p te d t o m od if y t h e E-ri ng t hrough i n tr oduc ti on o f an e l e ctr on -wit hd rawi ng g r oup at t h e α po siti on in a n e f fort t o ove r co m e t he i ns ta b ilit y o f t h e E-ri ng w h ile mai n tai n i ng t h e b i nd i ng capab ilit y o f t he ca m p t o t h eci n a n al og t o t h e T op1 -DNA clea v a ge c o m p le x. Co ll ec ti ve l y ca ll ed ho m o cam p t o t h eci n a n al og s , tw o h a v e b ee n teste d in c li n i ca l tri a l s and i n cl ud e d ifl o m o teca n a nd el o m o teca n . T he do se - limiti ng t ox i c it y i n t he P h ase I st udy o f el o m o teca n was n e u tr op e nia. A f i v e -me m be r E-ri ng de ri va ti v e h as als o b ee n d e v el op e d a nd h as reac h e d a P h ase 1 c li n i ca l tri a l . Non ca mp t o t hec i n T opo i so m er ase I I nh i b it o rs

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S ub se quen t sea r ches f o r l ess tox ic d r ug s a nd f o rm u lati on s le d t o t h e a pprov a l o f li poso m a l doxo r ub ici n, i d ar ub ici n, a nd e p ir ub ici n.

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An t hr ac yc li nes a r e fl a t , p l anar m o lec u les t h at are relati v el y hyd r ophob ic . Th e qu i none s tr uc t u r e o f an t h rac y cli n es (see e nh a n ces t h e catal y si s o f ox i da ti on -r educ ti on reacti on s , t h ere by p r o m o ti ng t h e g e n era tion of oxyg e n fr ee r ad i ca l s, wh i ch ma y b e i nvo l v e d i n a n tit u m o r effects as w ell as t h e c a r d i o t ox i c it y assoc i a t ed wit h t h ese d r ug s A n t h rac y cli n es ar e als o s ubs tr a t es f o r P- g l ycop r o tei n a nd Mr p - 1, a nd d r ug e f fl ux is t hough t to b e a ma jo r d r ug r es i s t ance de termi n a n t Doxorub i c i n i s ava il ab l e i n a sta nd ar d salt f o rm a nd as a li po s o mal for m u la t i on. F DA -l abe l ed i nd icati on s f o r sta nd ar d doxo r ub ici n i n cl ud e ac u te l ymphocy ti c l euke mi a ( A LL) , AML , c h r on ic l y m pho i d le uk emia , Hodgk i n l y m pho m a, non - Ho d gk i n l y m pho ma , ma n tle cell l y m pho ma , m u lti p le m ye l o m a, m ycos i s f ungo i d es , Ka po si sarc o ma , b reast ca n cer ( a d j uv a n t t he r apy and advanced ) , a dv a n ce d p r o state ca n ce r , a dv a n ce d g ast r ic cance r , E w i ng sa r co m a, t hy r o i d ca n ce r , a dv a n ce d n e ph r ob last o m a, a dv a n ce d neu r ob l as t o m a, adv a n ce d non– small-cell l ung ca n ce r , a dv a n ce d ov a r ia n cance r , advanced tr an siti on al cell b la dd er ca n ce r , cer v ical ca n ce r , a nd L a nge r hans ce ll t u m o r s. D oxo r ub ici n h as acti v it y i n o t h er mali gn a ncies as w ell , i nc l ud i ng so ft ti ssue sarc o ma , o ste o sarc o ma , carci no i d, a nd li v e r ca n ce r ( . Doxo r ub ici n is t yp icall y a d mi n istere d at a r ec o mm ended dose o f 30 t o 75 m g / m 2 e v er y 3 wee k s i n tra v e nou sl y . Maj or a cu t e t ox i c iti es o f doxo r ub ici n i n cl ud e m y el o s upp ressi on, m u c o sit is, al op ecia , nausea, and vo miti ng. M y el o s upp ressi on is t h e ac u te do se-limiti ng t ox i c it y . O t he r t ox i c ities , i n cl ud i ng d iarr h ea , n a u sea , vo miti ng, m u c o sit is, and a l opec i a, a r e do se a nd sc h e du le relate d. Pr ophy lactic a n tieme t i cs a r e r ou ti ne l y g i ven wit h bo l u s do ses o f doxo r ub ici n, a nd l onge r i nfu si ons a r e assoc i a t ed w it h less n a u sea a nd less car d i o t ox icit y . Patie n t s s hou l d al so be wa r ned t o exp ect t h eir u ri n e t o re dd e n after d r ug a d mi n is t r a ti on. Doxo r ub i c i n i s a po te n t v esica n t , a nd e x tra v asati on ca n l ead t o se v e re nec r os i s o f sk i n and l o cal tiss u es , re qu iri ng s u r g ical d e b ri d eme nt a nd s k i n g r a ft s. I n f us i ons v i a a ce n tral v e nou s cat h eter are rec o mme nd e d. O t h e r t ox i c iti es o f doxo r ub i c i n i n cl ud e ra d iati on recall a nd t h e ris k o f d e v el oping seconda r y l euke mia . Ra d iati on recall is a n i n flammat o r y r eacti on a t s it es o f p r ev i ous r ad iati on a nd ca n lea d t o p ericar d itis , p le u ra l

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e f fu si on, and sk i n r ash. S eco n d ar y le uk emias are t hough t t o b e a res u lt o f b ala n ce d tr ans l oca ti ons t ha t r e s u lt fr o m T op2 po is on i ng by t h e a n t hr acy c li nes, a l be it t o l esse r d e g ree t h a n o t h er T op2 po is on s , s u c h as t he e p i podophy ll o t ox i ns ( see t he f o ll o wi ng ) . An t hr ac yc li nes a r e c l ea r ed mai n l y by meta bo lism t o less acti v e f o rms a nd by b iliar y exc r e ti on. L ess t han 10 % o f t h e a d mi n istere d do se is cleare d b y t h e k i dneys. Dose r educ ti ons s hou l d b e ma d e i n p atie n ts wit h ele v ate d p lasma b ilir ub i n. Doxo r ub i c i n s hou l d b e do se re du ce d by 50 % f o r p las ma b ili rub in concen tr a ti ons r ang i ng fr o m 1.2 t o 3.0 m g / d L , by 75 % f o r v al ues of 3.1 t o 5.0 m g / d L , and w it h hel d f o r v al u es g reater t h a n 5 m g / d L . L i po s o m a l Doxo r ub i c i n Doxorub i c i n i s a l so ava il ab l e i n a po l y et hy le n e g l y c o l (PEG) y late d li po s o m a l f o rm , wh i ch a ll ows f o r e nh a n ceme n t o f d r ug d eli v er y . Use o f li po s o m a l doxo r ub i c i n has be e n ass o ciate d wit h less car d i o t ox icit y e v e n at do ses ex ceed i ng 500 m g / m 2 . A dd iti on all y , li po s o mal doxo r ub ici n produ ces l ess nausea and vo miti ng a nd relati v el y mil d m y el o s upp ressi on c o m p a red t o doxo r ub i c i n. Uniqu e t o t h e li po s o mal f o rm u lati on is t h e ris k o f h a nd–foo t synd r o m e and an acu te i n f u si on reacti on ma n ifeste d by fl u s h i ng, dy s pn ea , ede m a, f eve r , ch ill s, ras h, b r on c ho s p asm , a nd hyp erte n si on. T hese i nfu si on r eac ti ons a r e r e l a t ed to t h e rate o f i n f u si on ; t h eref o re , t h e r ec o mm ended ad mi n i s tr a ti on sc h e du le is set at a n i n itial rate o f 1 m g p er mi nu te f o r t he fir s t 10 t o 15 m i nu tes . T h e rate ma y b e sl o wl y i n crease d t o c o m p let e i n f us i on ove r 60 mi nu tes if no reacti on o cc u rs . T yp ical do si ng sc h e du l es i nc l ude 50 m g / m 2 i n tra v e nou s i n f u si on e v er y 4 wee k s f o r f ou r c our ses i n ova ri an cance r , 20 m g /m 2 i n tra v e nou s i n f u si on e v er y 3 wee ks in AID S -re l a t ed Kapos i sa r co ma , a nd 30 m g / m 2 i n tra v e nou s i n f u si on i n c o m b i na ti on w it h bo rt ezo mi b t o b e g i v e n on d a y s 1, 4, 8, a nd 1 1 e v er y 3 w ee k s i n m u lti p l e m ye l o m a. D a unorub i c i n D es p ite it s che mi ca l s imil a rit y (see ) , d a uno r ub ici n is c on si d er ab l y l ess ac ti ve i n sol i d t u m o rs c o m p are d t o doxo r ub ici n. It is F DA a pprov e d f o r t he tr ea tm en t o f ALL a nd AML . Da uno r ub ici n is t yp icall y

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a d mi n is te r ed v i a i n tr avenous pu s h ov er 3 t o 5 mi nu tes at a do se o f 30 t o 45 m g /m 2 pe r day on 3 consecu ti v e d a y s i n c o m b i n ati on c h em o t h era p y . F or i ndu cti on t he r apy f o r ped i a tric ac u te l y m phob lastic le uk emia , d a uno r ub i cin is do se d a t 25 m g / m 2 i n tr avenou sl y i n c o m b i n ati on wit h v i n cristi n e a nd pr e dn is one. I n ch il d r en l ess t h a n 2 y ears o f a g e o r i n t ho se w ho h a v e a body s urf ace ar ea l ess t han 0.5 m 2 , c u rre n t rec o mme nd ati on s are b ase d on body mass i ndex ( 1 m g / kg ) r a t he r tha n body s u rface area . A h i gh er do se o f d a unorub i c i n a t 60 m g / m 2 per d a y t o 90 m g / m 2 p er d a y i n tra v e nou sl y f o r 3 c on sec u ti ve days i s cu rr en tl y r ec o mme nd e d as p art o f t h e i ndu cti on c o m b i na ti on r eg im en f o r t he t reatme n t o f ac u te m y el ob lastic le uk emia . D a unorub i c i n has s imil a r t ox icities t o doxo r ub ici n, i n cl ud i ng m y el o s upp r ess i on, ca r d i ac t ox icit y , n a u sea , vo miti ng, al op ecia , a nd is al so a v esica n t . Dauno r ub i c i n i s meta bo lize d by t h e li v er a nd und e r go es s ub sta n ti a l e limi na ti on by t he k i dn e y s , re qu iri ng do se re du cti on s f o r bo t h r e n al a n d hepa ti c dys f unc ti on. A 50 % do se re du cti on is rec o mme nd e d f o r eit h e r s e r u m c r ea ti n i ne o r b ilir ub i n g reater t h a n 3 m g / d L , a nd a 25 % r e du cti on i n dose f o r b ilir ub i n c on ce n trati on s ra ng i ng fr o m 1.2 t o 3.0 m g / dL. Ep i rub i c i n Ep i rub i c i n i s an ep im e r o f do x o r ub ici n (see wit h i n crease d li poph il ic it y . It i s F DA app r ov e d f o r a d j uv a n t t h era py o f b reast ca n cer but is als o used i n co m b i na ti on f o r t h e treatme n t o f a v ariet y o f mali gn a n cie s. Ep i rub i c i n i s ad mi n i s t e r ed i n tra v e nou sl y at do ses ra ng i ng fr o m 60 t o 120 m g /m 2 eve r y 3 t o 4 weeks. Epir ub ici n h as a similar t ox icit y p r o file t o doxorubic i n bu t i s ove r a ll be tter t o lerate d. In a dd iti on t o be i ng conve rt ed t o a n e no l by a n al do se re du ctase , e p ir ub i cin h as a un i que s t e ri c o ri en t a ti on o f t h e C- 4 hyd r oxy l g r oup t h at all o ws it t o se rv e as a subs tr a t e f o r con j ug ati on reacti on s me d iate d by li v er g l u c uronosy ltr ans f e r ases and s u lfatases . As s u c h, do se a d j u stme n ts are r ec o mm ended i n t he se tti ng o f h e p atic dy sf un cti on. F o r p atie n ts wit h ser um b ili rub in o f 1.2 t o 3 m g / d L o r as p artate ami no tra n sferase o f 2 t o 4 times the upp e r limit o f no rm a l , a 50 % do se re du cti on is rec o mme nd e d. F o r p atie nts w it h b ilir ub i n g r ea t e r t han 3 mg / d L o r as p artate ami no tra n sferase g reater t h a n 4 tim es t he uppe r limit of no rmal , a do se re du cti on o f 75 % is

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r ec o mm ended. Due t o limit ed d ata , no s p ecific do se rec o mme nd ati on s a re c urr e n tly ava il ab l e f o r pa ti en t s wit h re n al im p airme n t , alt hough c u rre n t r ec o mm enda ti ons a r e f o r con si d erati on o f do se a d j u stme n ts i n p atie n ts with se ru m cr ea ti n i ne g r ea t e r t han 5 m g / d L . Id a rub ici n Id a rub ici n i s a syn t he ti c de ri v ati v e o f d a uno r ub ici n, bu t lac k s t h e 4 -met hoxy g r oup ( see . It is FDA a pp r ov e d as p art o f c o m b i n a tion c h em o t he r apy r eg im en f o r AM L a nd is als o acti v e i n ALL . It is g i v e n i n t r a v e nous l y a t a dose o f 12 m g / m 2 f o r 3 c on sec u ti v e d a y s , t yp icall y i n c o m b i na ti on w it h cy t a r ab i ne. I d ar ub ici n h as similar t ox icities as d a unorub i c i n. It s p rim a r y ac ti v e meta bo lite is i d ar ub ici no l , a nd elimi n at ion is mai n l y t h r ough t he b ili a r y sy stem a nd, t o a lesser e x te n t , t h r ough re n a l e x c r eti on. A 50 % dose r educ ti on is rec o mme nd e d f o r ser u m b ilir ub i n o f 2.6 t o 5 m g /dL and i da r ub i c i n shou l d no t b e g i v e n if t h e b ilir ub i n is g reater t h a n 5 m g / d L . Add iti ona ll y , do se re du cti on s i n re n al im p airme n t are a dv ise d, bu t spec ifi c gu i de li ne s are no t a v aila b le . Ca rd iac T ox i c it y o f An t h r acy cli n es An t hr ac yc li nes a r e r espons i bl e f o r car d iac t ox icities , a nd s p ecial c on si d er a ti ons a r e necessa r y t o mi n imize t h is se v ere si d e e f fect . Ac u te doxorubic i n ca r d i o t ox i c it y i s r e v ersi b le , a nd cli n ical si gn s i n cl ud e tac hy car d i a, hypo t ens i on, e l e ctr o car d i og ram c h a ng es , a nd arr hy t h mias . It d e v el op s du ri ng o r w it h i n day s o f a n t h rac y cli n e i n f u si on, a nd its i n ci d e nce ca n b e si gn ifi can tl y r educed by sl o wi ng doxo r ub ici n i n f u si on rates . C hron ic and de l ayed ca r d i o t ox icit y is m o re c o mm on a nd m o re se v ere b eca u se it i s irr eve r s i b l e. Ch ro n ic car d i o t ox icit y wit h c ong esti v e h eart f ail ur e p eaks a t 1 t o 3 m on t hs bu t ca n o cc u r e v e n y ears after t h era p y . M yo ca r di a l da m age has been s ho w n t o o cc u r by se v eral mec h a n isms . T he classical m echan i s m i s by t he d irect g e n erati on o f reacti v e oxyg e n s p eci es ( R O S ) du ri ng t he e l ec tr on tr an sfer fr o m t h e semi qu i non e t o qu i non e m o ietie s o f t he an t h r acyc li ne , w h ic h lea d s t o m yo car d ial d ama g e . RO S ca n als o be gene r a t ed by mit o c hond rial d ama g e res u lti ng fr o m d r ug -me d iated i nac ti va ti on o f t he ox i d ati v e pho s pho r y lati on c h ai n b eca u se

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doxorubic i n accu m u l a t es no t on l y i n c h r o mati n, bu t als o i n mit o c hond ri a . A r ecen t s t udy h as als o relate d doxo r ub ici n ca rd i o t ox i c it y t o t he po i son i ng o f T op2 β clea v a g e c o m p le x es i n m yo ca rd i ocy t es . E ndo m yo car d ial b i op s y is c h aracterize d by a pr e do mi nan t fi nd i ng o f m u ltif o cal areas o f p atc hy a nd i n terstitial fi b r o si s ( stellate sca r s ) and occas i ona l v ac uo late d m yo car d ial cells (A d ria cells) . M yo c y te hype rtr ophy and de ge n erati on, l o ss o f cr o ss-striati on s , a nd t h e a b se n ce o f m yoca r d iti s a r e a l so c h aracteristic o f t h is d ia gno sis . T h e i n ci d e nce o f ca r d i o m yopa t hy is relate d t o bo t h t h e c u m u lati v e do se a nd the sc h e du l e o f ad mi n i s tr a ti on, and p re d is po siti on t o car d iac d ama g e i n cl udes a pr e v i ous h i s t o r y o f hea rt d i se ase , hyp erte n si on, ra d iati on t o t h e me d iast inu m , age g r ea t e r t han 65 y ears o r young er t h a n 4 y ears , p ri o r u se of a n t hr a cyc li nes o r o t he r ca r d iac t ox i n s , a nd c o a d mi n istrati on o f o t h er c h em o t he r apy agen t s ( e.g., pa clita x el , c y cl opho s ph ami d e , o r t r ast u z u m ab ) S equen ti a l a d mi n istrati on o f p aclita x el f o ll o we d by doxorubic i n i n b r eas t cance r p atie n ts is ass o ciate d wit h car d i o m yop at hy at t o tal doxo r ub i c i n doses abov e 340 t o 380 m g / m 2 , w h ereas t h e re v erse se qu e n c e o f d r ug ad mi n i s tr a ti on d i d no t y iel d t h e same s y stemic t ox iciti es at t h ese doses . When doxo r ub ici n is g i v e n i n a l o w- do se wee k l y re g i men (10 t o 20 m g /m 2 pe r week ) o r by sl o w c on ti nuou s i n f u si on ov er 96 hou r s, c u m u lati ve doses o f m o r e t han 500 m g / m 2 ca n b e g i v e n. D o ses o f e p i rub ici n l ess t han 1,000 m g / m 2 a nd d a uno r ub ici n less t h a n 550 m g / m 2 a r e c on si de r ed sa f e. Add iti on all y , li po s o mal doxo r ub ici n is ass o ciate d w ith less ca rd i ac t ox i c it y . Ca rd iac f unc ti on can be m on it o re d du ri ng treatme n t wit h a n t h rac y cli n es by elect ro car d i og r aph y , echoca r d i og ra ph y , o r ra d i onu cli d e sca n s . N u mer ous st ud ies have es t ab li shed t he d a ng er o f em b ar k i ng on a n t h rac y cli n e t h era py i n p atie n t s w it h unde rl y i ng ca r d iac d isease (e .g., a b aseli n e left v e n tric u l a r ejecti on fr ac ti on o f l ess t han 50 %) a nd o f c on ti nu i ng t h era py after a do c u me n t ed dec r ease i n t he e jecti on fracti on by m o re t h a n 10 % (if t h is d ec r eas e f a ll s be l ow t he l owe r limit o f no rmal) . Beca u se a n t h rac y cli n e-i ndu ce d ca r d i o t ox i c it y has be e n relate d t o t h e g e n erati on o f free ra d icals , e f for ts have been a im ed a t a tte nu ati ng t h is effect t h r ough t h e ta r g eti ng o f r e dox r e sponse and r educ ti on i n ox i d ati v e stress . De x raz ox a n e is a metal c h elat or t ha t dec r eases t he m yo car d ial t ox icit y o f doxo r ub ici n i n b reast

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ca n ce r pa ti en t s. I n t wo m u lti c e n te r , doub le- b li nd st ud ies , a dv a n ce d b rea st ca n ce r pa ti en t s we r e r ando mi z e d t o c h em o t h era py wit h d e x raz ox a n e o r a p lace bo; dex r azoxane was sho w n t o h a v e a car d i op r o tecti v e e f fect b ase d on se r ial , non i nvas i ve ca r d i ac t es ti ng du ri ng t h e c ou rse o f t h e trial a nd is a pprov e d f o r t ha t use by t he FDA . De x raz ox a n e c h elates ir on a nd c oppe r , t h e r e by i n t e rf e ri ng w it h t he re dox reacti on s t h at g e n erate free ra d icals a nd d ama g e m yoca r d i a l li p i ds. No ta b l y , d e x raz ox a n e is als o a T op2 catal y tic i nh i b it or ( see , wh ic h po te n tiall y mi gh t mi n imize t h e t h era p e utic acti v it y o f an t h r acyc li nes by i n terferi ng wit h t h e tra pp i ng o f T op2 clea vage c o m p le xes by an t h r acyc li nes . , Ot h er a g e n ts c u rre n tl y i n u se i n cl ud e β- b l o c k e rs and s t a ti ns. A r ecen t meta-a n al y sis o f 12 ra ndo mize d c on tr o lle d t r ials a n d 2 obse r va ti ona l s t ud ies i nvo l v i ng t h e u se o f a g e n ts t o p re v e n t t he ca rd i o t ox i c it y assoc i a t ed w ith a n t h rac y cli n es d em on strate d relati v el y simila r e f fi cacy r ega r d l ess o f wh ic h p r ophy lactic treatme n t was u se d . An t hr ac ened i ones Mit ox a n tr one ( see is c u rre n tl y t h e on l y cli n icall y a pp r ov e d a n t hr ace ned i one. Co m pa r ed t o a n t h rac y cli n es , mit ox a n tr on e is less ca rd i o t ox i c ow i ng t o a dec r ea se d a b ilit y t o und er go ox i d ati on -re du cti on r eacti ons and f o rm fr ee r ad i ca ls . Mit ox a n tr one i s F DA app r oved f o r t h e treatme n t o f a dv a n ce d ho rm on e- r e fr act ory p r os t a t e cance and AML It is t yp icall y a d mi n istere d i n t r a v e nous l y a t a dose o f 12 t o 14 m g / m 2 e v er y 3 wee k s i n t h e treatme nt o f pro state cance r , and a t a dose o f 12 m g /m 2 i n c o m b i n ati on wit h c y t o si n e a r a b i nos i de f o r 3 days i n t he t reatme n t o f AML . T ox iciti es a r e gene r a ll y l ess sev ere c o m p are d t o doxo r ub ici n a nd i n cl ude m y el o s upp r ess i on, nausea, vo miti ng, al op ecia , a nd m u c o sitis . Car d iac t ox icit y can be seen a t cu m u lati v e do ses g reater t h a n 160 m g / m 2 .

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Mit ox a n tr one i s r ap i d l y c l ea r ed fr o m t h e p lasma a nd is h i gh l y c on ce n tra ted i n tiss u e s. T he m a j o rit y o f t h e d r ug is elimi n ate d i n t h e feces , wit h a sma ll am oun t unde r go i ng r ena l excr eti on. D o se a d j u stme n ts f o r h e p atic dy s fun c t i on a r e r eco mm ended, bu t f o rmal gu i d eli n es are c u rre n tl y no t a v aila b le .

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D acti no m yc i n D acti no m yc i n was t he fir s t an ti b i o tic s ho w n t o h a v e a n tit u m o r acti v it y

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a nd c on si s t s o f a p l ana r phenox az on e ri ng attac h e d t o tw o p e p ti d e si d e c h ai n s . T h i s un i que s tr uc t u r e all o ws f o r ti gh t i n tercalati on i n t o DNA b et w ee n ad j acen t guan i ne–cy t o si n e b ases , lea d i ng t o T op2 a nd T op1 po is on i ng and tr ansc ri p ti on i nh i b iti on . Dacti no m y ci n was on e o f t h e f i r st drug s s hown t o be tr anspo rt ed by P- g l y c op r o tei n, a nd re p rese n ts t h e ma jo r mec h a nis m o f r es i s t ance . D acti no m yc i n i s F DA app r oved f o r Ewi ng sarc o ma , g estati on al t rophob l as ti c neop l as m , metastatic non semi no mat ou s testic u lar ca n ce r neph r ob l as t o m a, a nd r h a bdo m yo sarc o ma . T yp icall y , it i s a d mi n is te r ed i n tr avenous l y a t do ses o f 15 μg / kg f o r 5 d a y s i n c o m b i n ati on w it h o t he r che m o t he r apeu ti c a g e n ts f o r t h e treatme n t o f n e ph r ob last o ma, rh a bdo m yosa r co m a, and E w i ng sarc o ma; at do es o f 12 μg / kg i n tra v e nously as a si n gl e agen t i n t he tr ea tme n t o f g estati on al tr ophob lastic n e op lasias; a nd at doses o f 1,000 μ g / m 2 i n tra v e nou sl y on d a y 1 as p art o f a c o m b i na ti on r eg im en w it h cyc l opho s ph ami d e , b le o m y ci n, v i nb lasti n e , a nd cis p latin i n t he tr ea tm en t o f metastatic non semi no mat ou s testic u lar ca n c e r . T ox iciti es i nc l ude m ye l osuppr essi on, v e no - o ccl u si v e d isease o f t h e li v e r , n a u sea , vo miti ng, a l opec i a, e r y t h ema , a nd ac n e . A dd iti on all y , similar t o doxorubic i n, dac ti no m yc i n c a n ca u se ra d iati on recall a nd se v ere tiss u e n ec ro sis i n cases o f ex tr avasa ti on. Dacti no m y ci n is lar g el y e x crete d un c h a nged i n t he f eces and ur i n e . G u i d eli n es f o r do si ng i n p atie n ts wit h im p ai r e d r ena l o r li ve r f unc ti on are c u rre n tl y no t a v aila b le . Ep i podophy ll o t ox i ns Ep i podophy ll o t ox i ns a r e g l yco si d e d eri v ati v es o f podophy ll o t ox i n, a n a n timic r ot ubu l e agen t ex tr ac t ed fr o m t h e ma nd ra k e p la n t . T w o d eri v ati ves, d emet hy l a t ed on t he pendan t r i ng (see R 1 i n , et opo si d e a nd te n i po si de we r e shown t o p rimaril y f un cti on as T op2 po is on s rat h er t h a n t hrough an timi c r o t ubu l e m ech a n isms . E p i podophy ll o t ox i n s po is on T op2 t h r ough a m echan i s m di sti n ct fr o m t h at o f a n t h rac y cli n es a nd o t h er DNA i n t e r ca l a t o r s w it hou t i n tercalati ng i n t o no rmal DNA i n t h e

nan nan

a b se n ce o f T op2. T he r e f o r e, t h e y are “clea n er” T op2 i nh i b it o rs t h a n t h e a n t hr acy c li nes, an t h r acened i on es , a nd d acti no m y ci n. H o we v e r , et opo si de a nd te n i pos i de tr ap T op2 c l eav a g e c o m p le x es by b ase stac k i ng i n a ter na r y c o m p le x a t t he i n t e rf ace o f t he DNA a nd t h e T op2 ho m od ime r . Mec h a n i s m s t ha t have been im p licate d i n resista n ce t o et opo si d e i n cl ud e drug e f flux, because ep i podophy ll o t ox i n s are s ub strates f o r P- g l y c opro t e i n ; a lt e r ed l oca l i zati on o f T op2α ; d ecrease d cell u lar e xpr essi on o f T op2 ; and im p aire d pho s pho r y lati on o f T op2 E t opo si de E t opo si de ( see ) i s a v aila b le i n i n tra v e nou s a nd o ral f o rms . It is F DA a pp r oved f o r t he tr ea tm en t o f small-cell l ung ca n ce r a nd refractor y testic u lar cance r It a l so ha s acti v it y i n h emat o l og ic mali gn a n cies a nd v a r i ou s so li d t u m o r s. T he i n tra v e nou s f o rm is g e n erall y a d mi n istere d at do ses of 35 t o 50 m g / m 2 f o r 4 t o 5 d a y s e v er y 3 t o 4 wee k s i n c o m b i n ati on t h e r a py f o r s m a ll- ce ll l ung can ce r , a nd 50 t o 100 m g /m 2 f o r 5 d a y s e v er y 3 t o 4 w e eks i n co m b i na ti on t h era py f o r refract o r y testic u lar ca n ce r . T h e dose of or al et opos i de i s usua ll y twice t h e i n tra v e nou s do se . Oral b i o a v aila b ili ty is h i gh l y va ri ab l e due t o depend e n ce on i n testi n al P- g l y c op r o tei n . Th e do se-limiti ng t ox i c it y f o r et opo si d e is m y el o s upp ressi on, wit h w h it e b l ood c e ll coun t nad ir s t yp i cal l y o cc u rri ng on d a y s 10 t o 14. Thro m bocy t open i a i s l ess co mm on t h a n le ukop e n ia . A dd iti on all y , mil d to m od e r at e nausea, vo miti ng, d iarr h ea , m u c o sitis , a nd al op ecia are ass o ci ated w it h et opos i de. A m ong t opo is o merase i nh i b it o rs , e p i podophy ll o t ox i n s have t h e gr ea tes t assoc i a ti on w it h s ec ond ar y mali gn a n cies , wit h et opo si d e h a v i ng t he h i ghes t ri sk, w it h a n estimate d 4 % 6 - y ear c u m u lati v e ris k .

nan nan

nan nan

T e n i po s ide T e n i po s ide con t a i ns a t h i oph e n e g r oup i n p lace o f t h e met hy l g r oup on t he g l u c o se m o i e t y o f e t opos i de ( . T e n i po si d e is FDA a pp r ov e d f o r r e fr act ory ped i a tri c A LL . I n p e d iatric ALL st ud ies , do ses ra ng e d fro m 165 m g / m 2 i n tr avenous l y i n c o m b i n ati on wit h c y tara b i n e t o 250 m g /m 2 i n tr avenous l y week l y in c o m b i n ati on wit h v i n cristi n e a nd pr e dn is one. Simil a r t o e t oposid e , t h e do se-limiti ng t ox icit y o f te n i po si de is m y el o s upp r ess i on. Add iti ona l t ox icities i n cl ud e mil d -t o -m od erate n a u sea , vo miti n g , d i a rr hea, a l opec i a, a nd sec ond ar y le uk emia . T e n i po si d e is ass o ciate d w it h g r ea t e r fr equ e n c y o f hyp erse n siti v it y reacti on s c o m p are d to et opo si de. T e n i po s ide i s 99 % bound t o a l bu mi n a nd, as c o m p are d t o et opo si d e , und e r goes hepa ti c m e t abo li s m m o re e x te n si v el y a nd re n al cleara n ce les s e x te n si ve l y . No spec ifi c gu i d eli n es are c u rre n tl y a v aila b le on do se a d j u stme n t s f o r r ena l o r hepa tic dy sf un cti on. THE R A P Y - R EL A TE D SE C ONDA R Y ACUTE LEUKEMIA On e of th e m a j o r co m p li ca ti on s o f T op2 i nh i b it o r t h era p ies , es p eciall y f o r et opo si de and mit oxan tr one, is ac u te sec ond ar y le uk emia , w h ic h o cc u rs in a pprox im a t e l y 5 % o f pa ti en t s. T h era py -relate d AMLs (t-AML) are c h a r acteri zed by t he ir r e l a ti v el y ra p i d on set (t h e y ca n o cc u r on l y a few m on t h s a ft e r t he r apy ) and t he p rese n ce o f rec u rre n t b ala n ce d tra n sl o cati ons i nvo l v i n g t he mi xed li neage l euk emia (MLL) l o c u s on 1 1q23 a nd ov er 50 p a r t n e r genes T he m o l ecu lar mec h a n ism is li k el y fr o m t h e d isj o i n i ng o f t wo drug -tr apped T op2 c l eav a g e c o m p le x es on d i f fere n t c h r o m o s o mes ( see ) i n r e l a ti onsh i p w it h tra n scri p ti on c o llisi on s a nd ille g itimate r ele g ati on . T op2 β , r a t he r t h a n T op2α, h as b ee n im p licate d i n t h e g e n e r atio n o f t hese d i s j o i ned c lea v a g e c o m p le x es . F UTU RE D I R E C TI ON S C urr e n t cha ll enges i n t he deve l op me n t o f t opo is o merase i nh i b it o rs lie i n the i nh e r e n t che mi ca l i ns t ab ilit y o f c u rre n t a nd esta b lis h e d a g e n ts . I n a dd iti on t o r ece nt deve l op m en t s des i gn e d t o e nh a n ce t h e sta b ilit y wit h semis yn t hetic

nan nan

a n al og s and t he deve l op m en t o f nov el d eli v er y s y stems i n a n eff o rt t o ac h ie v e h i ghe r i n tr a t u m o r a l con ce n trati on s , atte n ti on is als o b ei ng f o c u s ed on ta r g eti ng o t he r t opo i so m e rase is o e n z y mes . Dri v i ng t h is tre nd h as b een t h e r ece n t e l uc i da ti on o f t he r o le o f T op2 β i nh i b iti on i n t h e d e v el op me n t o f t r eatme n t-r e l a t ed ca r d i o t ox i c it y a nd sec ond ar y AML . I n a dd iti on t o c o m b i na ti on che m o t he r apy re g ime n s alrea dy i n u se , attem p ts h a v e al so b ee n ma de f o r t he sequen ti a l i nh i b iti on o f T op1 a nd T op2. Base d on earl y pr ecli n i ca l m ode l s sugges ti ng s yn e r gy wit h se qu e n tial i nh i b iti on o f T op1 a nd T op2, phase 1 s t ud i es h a v e e v al u ate d t h e se qu e n tial a d mi n istrati on of t opo te can and e t opos i de i n e x te n si v e-sta g e small-cell l ung ca n cer a nd ov a r ia n cance r , w it h s i gn ifi can t m y el o s upp ressi on as t h e do se-limiti ng t ox icit y . F u t u r e r a ti ona l d r ug c o m b i n ati on s i n cl ud e tar g eti ng DNA r e p ai r pa t hways i n co m b i na ti on wit h T op1 i nh i b iti on, alt hough f u rt h er c h a r acteri za ti on i s needed o f th e s p ecific DNA re p air a nd stress res pon se p at hw ay s i nvoked i n r espons e t o DNA d ama g e as a res u lt o f T op1 i nh i b itio n. Howeve r , one such attem p t o f c o m b i n i ng t opo teca n wit h v eli p a r i b, a s m a ll m o l ecu l e i nh i b it o r o f po l y (ADP-ri bo se) po l y merase , was poor l y tol e r a t ed due t o s i gn ifica n t m y el o s upp ressi on, t hu s limiti ng t h e do ses of t opo t ecan t ha t cou l d b e safel y a d mi n istere d . M o lec u l a r cha r ac t e ri za ti on o f t u m o rs t o b etter d efi n e p atie n t selecti on a nd t h e d e v el op m en t o f pha rm acodyn amic b i o mar k ers t o m on it o r t h e res ponse t o t r eatm en t and t o op timi ze t h e c o m b i n ati on do se a nd sc h e du les is n ee ded for t h e fu rt he r c li n i ca l deve l op me n t o f t opo is o merase i nh i b it o rs . V ali d at ed assa y s have been deve l oped t o e v al u ate t opo is o merase 1 le v els a nd le v e ls of p l o s pho r y l a t ed h i s t one H2A X ( g amma-H 2 AX) as a mar k er o f DNA d ama g e r esponse t o t opo i so merase i nh i b iti on , a nd are b ei ng i n c orpo r a t ed i n cu rr en t phase I st ud ies o f i nd e no is oqu i no li n es . , R E F E R ENC ES 1. N iti ss J L . DNA t opo i so merase II a nd its g r o wi ng re p ert o ire o f b i o l og ic a l f unc ti ons. Na t Rev Ca n cer 2009 ; 9 ( 5 ): 327–337. 2. N iti ss J L . T a r ge ti ng DN A t opo is o merase II i n ca n cer c h em o t h era p y . N at Re v Cance r 2009 ; 9 ( 5 ): 338–350.

nan nan

22. Maede Y , S h imi zu H, Fuku s h ima T , et al . Di f fere n tial a nd c o mm on DNA r e pa ir pa t hways f o r t opo is o merase I- a nd II-ta r g ete d d r ug i n a g e netic DT40 repa ir sc r een pane l . Mo l Ca n cer T h er 2014 ; 13 ( 1 ): 214–220. 23. Huang S N, P o mmi e r Y , Marc h a nd C . T y r o s y l-DNA P ho s ph o d i es t e r ase 1 (T dp1 ) i nh i b it o rs . E xp ert O p i n i on T h er Pat 20 1 1 ; 21 ( 9 ): 1285–1292. 24. Zhang Y W , Rega ir az M , Seiler JA , et al . P o l y (ADP-ri bo se) po l y me r a se and X PF-E RCC1 p artici p ate i n d isti n ct p at h wa y s f o r t h e re pai r of t opo is o m e r ase I-i nduced DNA d ama g e i n mammalia n cells . N u cleic A ci d s R es 20 1 1 ; 39 ( 9 ): 3607–3620. 25. Kos t e r DA, P a ll e K, Bo t ES , et al . A n tit u m o r d r ug s im p e d e DNA un c o ili ng by t opo i so m e r ase I. Nat u re 2007 ; 448 ( 7150 ): 213–217. 26. Sor de t O, Redon C E , G u ir ou il h -Bar b at J , et al . Ata x ia tela ng iecta sia m u tate d ac ti va ti on by tr ansc r ip ti on - a nd t opo is o merase I-i ndu ce d DNA doub le -s tr and b r eaks. E MBO Re p 2009 ; 10 ( 8 ): 887–893. 27. Pommi e r Y , Z we lli ng L A , Matter n MR , et al . E f fects o f d imet hy l s u l fox i de and t h i ou r ea upon i n tercalat o r -i ndu ce d DNA si ng le-stra nd b re aks i n m ou s e l euke mi a (L 1210 ) ce lls . Ca n cer Res 1983 ; 43 ( 12 Pt 1 ): 5718–5724. 28. Long BH, Mus i a l S T , Brattai n MG . C o m p aris on o f c y t o t ox icit y a nd DNA breakage ac ti v it y o f cong e n ers o f podophy ll o t ox i n i n cl ud i ng VP 16 - 213 a nd VM26 : a quan tit a ti ve str u ct u re-acti v it y relati on s h i p. Bi o c h emis t r y 1984 ; 23 ( 6 ): 1 183– 1 188. 29. Ba n Y , Ho C W , Li n RK, et al . Acti v ati on o f a nov el ub i qu iti n -i nd e p e nden t p r o t easo m e pa t h wa y w h e n RNA po l y merase II e n c oun ters a pro tei n roadb l ock. Mo l Ce ll B i o l 2013 ; 33 ( 20 ): 4008–4016. 30. Long BH, Mus i a l S T , Brattai n MG . Si ng le- a nd doub le-stra nd D NA br ea k a ge and r epa ir i n hu m a n l ung a d e no carci no ma cells e xpo se d t o et opo si de and t en i pos i de. Can cer Res 1985 ; 45 ( 7 ): 3106–3 1 12.

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48. Ba ke r S D, He i de m an RL , Cr o m WR , et al . Cere b r o s p i n al fl u i d ph a r ma cok i ne ti cs and pene tr a ti on o f c on ti nuou s i n f u si on t opo teca n i n c h il dr e n w it h cen tr a l ne r vous s y stem t u m o rs . Ca n cer C h em o t h er P h arma col 1996 ; 37 : 195–202. 49. Sc h l uep T , Cheng J, K hi n K T , et al . P h armac ok i n etics a nd b i od ist r i bu ti on o f t he ca m p t oth eci n - po l y mer c on j ug ate I T - 101 i n rats a nd t u m o r -b e a ri ng mi ce. Cance r C h em o t h er P h armac o l 2006 ; 57 : 654–662. 50. Y oung C, S ch l uep T , Hw a ng J , et al . CRLX 101 (f o rmerl y I T - 101 ) -A nov el nanopha rm aceu ti ca l o f cam p t o t h eci n i n cli n ical d e v el op me n t . C u rr Bi o act C o m pd 20 1 1 ; 7 : 8–14. 51. W e i ss GJ, Chao J, Ne id h art JD , et al . First-i n - hu ma n ph ase 1 / 2 a tri al of CR LX101, a cyc l odex tri n -c on tai n i ng po l y me r -cam p t o t h eci n n a nopha rm aceu ti ca l i n pa ti en ts wit h a dv a n ce d s o li d t u m o r mali gn a n cies . Inv est New D r ugs 2013 ; 31 : 986–1000. 52. Un i ve r s it y o f Ch i cago. A ra ndo mize d ph ase II st udy o f IV T opo te can v e r s u s CR L X101 i n t he seco n d li n e treatme n t o f rec u rre n t small cell l ung ca n ce r . I den tifier: NCT 01803269. 53. Cer u l ean P ha rm a I nc. A ra ndo mize d, ph ase 2, st udy t o assess t h e sa f et y a nd ac ti v it y o f CR L X1 0 1, a n a nop article f o rm u lati on o f cam p t o t hec i n, i n pa ti en t s w ith a dv a n ce d non -small cell l ung ca n cer w ho h a v e f ai led one o r t wo p r ev i ou s re g ime n s o f c h em o t h era p y . Cli n ical T rial s Id e n ti f i e r: NC T 01380769. 54. Massachuse tt s Gene r a l H o s p ital . A P h ase II , 2 -sta g e T rial o f CR LX1 0 1 - 202 i n r ecu rr en t ov aria n, t ub al a nd p erit on eal ca n ce r . Cli n ical T ri a l s.gov I den tifi e r: NCT 01652079. 55. V e r go t e I B, Ga r c i a A, Mic h a J et al . Ra ndo mize d m u ltice n tre ph a se II t r ial c o m pa ri ng t wo schedu l es o f etiri no teca n p e go l (NKTR- 102 ) i n w omen w it h r ec u rr en t p l a ti nu m-r es i s ta n t/refract o r y e p it h elial ov aria n ca n ce r . J C lin On c o l 2013 ; 31 ( 32 ): 4060–4066.

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56. A wada A, Ga r c i a AA, Ch a n S et al . T w o sc h e du les o f etiri no teca n p e go l (NK T R - 102 ) i n pa ti en t s wit h p re v i ou sl y treate d metastatic b reast ca n ce r : a r ando mi zed phase 2 st ud y . La n cet O n c o l 2013 ; 14 ( 12 ): 1216–1225. 57. Ro swe ll P a r k Cance r I n stit u te . A ph ase II st udy o f si ng le a g e n t t opo is o m e r ase -I i nh i b it o r po l y mer c on j ug ate , Etiri no teca n Pe go l (NKTR- 102), i n pa ti en t s w it h r e l apsed small cell l ung ca n ce r . Cli n ical T rials Id e n ti f i e r: NC T 01876446. 58. Ab r a m son Cance r Cen t e r o f t h e U n i v ersit y o f Pe nn s y l v a n ia . P h as e 2 st udy of Etiri no t ecan P ego l (NKTR- 102 ) i n t h e treatme n t o f p atie n ts wit h metastati c and r ecu rr en t non -small cell l ung ca n cer (NSCLC) after fail u r e of 2nd l ine tr ea tm en t . C li n i ca l T rials I d e n tifier: NCT 01773109. 59. Nek t a r T he r apeu ti cs. A m u ltice n tre , op e n -la b el , ra ndo mize d, ph as e 2 st udy t o eva l ua t e t he e f fi cacy a nd safet y o f NKTR- 102 v ers u s iri no tecan in p atie n ts w it h second -li ne, iri no teca n - n ai v e , KRAS-m u ta n t , metastatic c o l or ectal cance r (m CRC ) . Cl i n ical T rials I d e n tifier: NCT 00856375. 60. Law r ence Rech t . A pha se II , si ng le arm , op e n la b el st udy o f NKT R - 102 i n bevac i zu m ab -r es i s t an t h i gh - g ra d e g li o ma . Cli n ical T rials I d e n tifier : N C T01663012. 61. Nek t a r T he r apeu ti cs. The BEACON st udy ( b reast ca n cer ou tc o m es w it h NK T R - 102 ): a phase 3 o p e n -la b el , ra ndo mize d, m u ltice n ter st udy o f NKT R -102 ve r sus tr ea tm en t of phy sicia n ’ s c ho ice (TPC) i n p atie n ts with l o call y recu rr en t o r m e t as t a ti c b reast ca n cer p re v i ou sl y treate d wit h a n a n t hr acy c li ne, a t axane and c a p ecita b i n e . Cli n ical T rials I d e n tifier: N C T01492101. 62. Ba s ili S , Mo r o S . Nove l cam p t o t h eci n d eri v ati v es as t opo is o meras e I i nh i b it ors. E xpe rt Op i n T he r Pat 2009 ; 19 : 555–574. 63. Ch o i CH, L ee Y Y , S ong TJ , et al . P h ase II st udy o f b el o teca n, a cam p t o t hec i n ana l ogue, i n co m b i n ati on wit h car bop lati n f o r t h e treatme nt of r ec ur r en t ova ri an cance r . Ca n cer 20 1 1 ; 1 17 : 2104–2 11 1.

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21 An timi c r o t ubu l e A g en t s

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21 An timi c r o t ubu l e A g en t s

21 An timi c r o t ubu l e A g en t s

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C hr ist ophe r J. Ho im es and L ynd sa y N . Harris M I CR O T UBU LES Mic ro t ubu l es a r e v it a l and dyn amic c y t o s k eletal po l y mers t h at p la y a c r itical r o l e i n ce ll d i v i s i on, s i gn ali ng, v esicle tra n s po rt , s h a p e , a nd po lar it y , wh ic h m ake t he m a ttr ac ti ve tar g ets i n a n tica n cer re g ime n s a nd d r ug d esi gn M i c r o t ubu l es a r e compo se d o f 13 li n ear p r o t o filame n ts o f po l y me rized α /β-t ubu li n he t e r od imers arra ng e d i n p arallel ar ound a c y li ndr ic a l ax i s and assoc i a t ed wit h re gu lat o r y p r o tei n s s u c h as mic ro t ubu l e - assoc i a t ed p r o t e i n s , ta u, a nd m o t o r p r o tei n s k i n esi n a nd dyn ei n T he spec ifi c b i o l og i c f un cti on s o f micr o t ubu les are du e t o t h eir un i qu e po l y m e ri za ti on dyna mics . T ubu li n po l y merizati on is me d iate d by a nu cleatio n - e l onga ti on m echan ism . O n e e nd o f t h e micr o t ubu les , terme d the p l u s e nd, i s k i ne ti ca ll y m o r e dyn amic t h a n t h e o t h er e nd, terme d t h e min us e nd ( ) . M i c r o t ubu l e dyn amics are gov er n e d by tw o p ri n ci p al pro cess es d ri ven by guanos i n e 5 ′-tri pho s ph ate (GTP) hyd r o l y sis: t r ea d milli ng o r po l ewa r d fl ux is t h e n et g r o wt h at on e e nd o f t h e mic ro t ubu l e and t he ne t sho rte n i ng at t h e oppo site e nd, a nd dyn amic i n sta b ilit y , wh i ch i s a p r ocess i n w h ic h t h e micr o t ubu le e nd s switc h s pon ta n e ous l y be t ween s t a t es o f sl o w s u stai n e d g r o wt h a nd ra p i d d e po l y m e ri za ti on . An timi c rot ubu le a g e n ts are t ubu li n - b i nd i ng d r ug s t h a t d i r ectl y b i nd t ubu l es, i nh i b it o rs o f t ubu li n -ass o ciate d scaff o l d k i n ases , o r i nh i b it ors o f t he ir assoc i a t ed mit o tic m o t o r p r o tei n s t o, u ltimatel y , d isr upt mic ro t ubu l e dyna mi cs. T hey a re b r o a d l y classifie d as micr o t ubu le sta b ilizin g o r mi c r o t ubu l e de sta b ilizi ng a g e n ts acc o r d i ng t o t h eir e f fects on t ubu li n p o l y m e ri za ti on. T AXAN ES

21 An timi c r o t ubu l e A g en t s

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T a x a n es we r e t he fir s t-i n - c l as s micr o t ubu le sta b ilizi ng d r ug s . A n cie n t me d ici na l a tt e m p t s a t ca r d i ac ph armac o t h era py u si ng material fr o m t h e t ox ic c on if e r ous yew tr ee, T axu s s pp., were li k el y relate d t o t h e p la n t ’ s al k al o i d t ax i ne e f f ec t on sod i u m a nd calci u m c h a nn els . T a x a n e c o m pounds a r e t h e resu lt o f a d r ug sc r een i ng o f 35,000 p la n t e x tracts i n 1963 t h at le d to t h e i d e n tifi ca ti on o f ac ti v it y fr o m t h e b ar k e x tract o f t h e Pacific y ew tre e, T a xu s b r ev if o li a. P ac lit axe l was i d e n tifie d as t h e acti v e c on stit u e n t wit h a r e por t of it s ac ti v it y i n ca r c i no ma cell li n es i n 1971 . M o ti v ati on t o i d e nti f y ta x a n es de ri ved fr o m t he m o re a bund a n t a nd a v aila b le n ee d les o f T a xu s b accata l ed t o t he deve l op m en t o f do ceta x el , w h ic h is s yn t h esize d by t he a dd iti on o f a s i de cha i n t o 10-d eacet y l b accati n III , a n i n acti v e ta x a n e pr ec ur so r T he t axane ri ngs o f p aclita x el a nd do ceta x el are li nk e d t o a n este r si de cha i n a tt ached t o t he C 13 po siti on o f t h e ri ng, w h ic h is esse n ti al for a n ti m i c r o t ubu l e and an tit u m o r acti v it y . Na nop article al bu mi n - bound p aclita x el ( nab - pac lit axe l) i s a f o rm u lati on t h at a vo i d s t h e s o l v e n t relate d si d e e f f e c t s o f non–wa t e r - so lu b le p aclita x el a nd do ceta x el . O v erc o mi ng do ceta x el and pac lit axe l ’ s sus ce p ti b ilit y t o t h e P- g l y c op r o tei n e f fl ux pump le d t o t he deve l op m en t o f cab azita x el . Ca b azita x el is s yn t h esize d by a dd i ng t wo m e t hoxy g r oups t o t h e 10 - d eacet y l b accati n III , w h ic h res u lt s in t h e i nh i b iti on o f t he 5′ -tri pho s ph ate –d e p e nd e n t effl ux pu m p o f P- g l y c opro t e i n. Paclita xe l i n iti a ll y r ece i ved re gu lat o r y a pp r ov al i n t h e U n ite d States i n 1992 for t he tr ea tm en t o f pa ti en ts wit h ov aria n ca n cer after fail u re o f firs t -li n e or s ubsequen t che m o t he r apy S ub se qu e n tl y , it h as been a pprov e d f o r seve r a l o t he r i nd icati on s , i n cl ud i ng a dv a n ce d b reast ca n cer a f te r a n t h r acyc li ne - based r eg ime n s ; c o m b i n ati on c h em o t h era py o f l y m ph nod e –pos iti ve b r eas t cance r i n t h e a d j uv a n t setti n g a dv a n ce d ov aria n ca n ce r i n co m b i na ti on w it h a p lati nu m c o m pound ; sec ond -li n e treatme nt o f AID S -re l a t ed Kapos i sa r co ma; a nd first-li n e treatme n t o f non– small-cell l ung ca nce r ( N S C L C ) i n co m b i n ati on wit h cis p lati n (see ) . I n a dd iti on t o t he U. S . F ood and Dr ug A d mi n istrati on (FDA) on -la b el i nd icati ons, pac lit axe l i s w i d el y u se d f o r se v eral o t h er t u m o r t yp es , s u c h as ca n ce r s o f unknown o ri g i n, b la dd e r , es oph a gu s , g astric , h ea d a nd n ec k, and ce rv ical cance r s. T he U. S . pa te n t f o r p aclita x el e xp ire d i n 2002, a nd a g e n e r ic fo rm o f pac lit axe l i s no w a v aila b le .

21 An timi c r o t ubu l e A g en t s

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Do ceta x el was fir s t app r oved f o r u se i n t h e U n ite d States i n 1996 f o r p atie n ts w it h m e t as t a ti c b r east ca n cer t h at p r og resse d o r rela p se d after a n t hr acy c li ne - based che m o t h era p y , w h ic h was later b r o a d e n e d t o a g e n e ral sec ond-l i ne i nd i ca ti on ( see ) , S ub se qu e n tl y , it recei v e d r e gu lat o r y app r ova l i n ad j uvan t c h em o t h era py o f sta g e II b reast ca n cer in c o m b i na ti on w it h Ad ri a m yc i n a nd c y cl opho s ph ami d e ( T AC) a nd first- line t r eatme n t f o r l oca ll y advanced o r metastatic b reast ca n ce r I n a dd iti on, do ceta x el has i nd i ca ti ons i n non resecta b le , l o call y a dv a n ce d, o r metasta tic N SC L C a ft e r f a il u r e o f o r i n c o m b i n ati on wit h cis p lati n t h era py ; metasta tic cast r ati on -r es i s t an t p r os t a t e c a n cer i n c o m b i n ati on wit h p re dn is on e ; fir st -li n e t r eatm en t o f gas tri c adeno carci no ma , i n cl ud i ng g astr o es oph a g eal j un cti on adenoca r c i no m a i n co m b i n ati on wit h cis p lati n a nd 5 -fl uo r ou ra cil (5-FU) ; and i nope r ab l e l oc all y a dv a n ce d s qu am ou s cell ca n cer o f t h e h ea d a nd neck i n co m b i na ti on wit h cis p lati n a nd 5 -FU (see . Do ceta x el ca m e o f f pa t en t i n 2010 a nd a g e n eric f o rm is a v aila b le . Mec h a n i s m o f Ac ti on Th e un i que m echan i s m o f ac ti on f o r p aclita x el was i n itiall y d efi n e d by Sc h i f f et a l i n 1979, who sho we d t h at it bound t o t h e i n teri o r s u rface o f t h e mic ro t ubu l e l u m en a t b i nd i ng sites c o m p letel y d isti n ct fr o m t ho se o f e x c h a ngeab l e G T P , co l ch i c i n e , podophy ll o t ox i n, a nd t h e v i n ca al k al o i d s .

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Th e ta xanes p r o f ound l y a lt e r t h e t ubu li n d iss o ciati on rate c on sta n ts at both e nd s of t he mi c r o t ubu l e, supp ressi ng trea d milli ng a nd dyn amic i n sta b ilit y . Do se -d e penden t t axane β-t ubu lar b i nd i ng i ndu ces mit o tic arrest at t h e G2 /M t rans iti on and i nduces cell d eat h. B y sta b ilizi ng micr o t ubu les , t h e y als o ca n s t a ll li gand - dependen t i n tracell u lar tra f fic k i ng, as s ho w n i n se qu est ra ti on o f t he and r ogen rece p t o r t o t h e c y t o s o l i n metastatic p r o st ate ca n ce r pa ti en t s tr ea t ed w it h do ceta x el , a nd is ass o ciate d wit h d ecrease d a ndrog e n -r egu l a t ed gene exp ressi on, s u c h as p r o state-s p ecific a n ti g e n (PSA). P e ri phe r a l neu r op at hy is a c o mm on do se-limiti ng t ox icit y ac ro ss t he an timi c r o t ubu l e ag e n ts a nd li k el y is a res u lt o f t h eir d irect e f f ect on mic ro t ubu l es. St ud i es hav e s ho w n t h at t h e y i nh i b it a n ter og ra d e a nd / o r r et rogr ad e f as t axona l tr anspo rt a nd ca n e xp lai n t h e d em y eli n ati ng “ dy i ng

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b ac k ” pa tt e r n seen and t he vu l n era b ilit y o f se n s o r y n e u r on s wit h t h e l ongest a xon al p r o j ec ti ons Rece n t ev i dence sugges t s t ha t micr o t ubu le i nh i b it o rs h a v e c o llateral e f f ects dur i ng int e r phase t ha t l ead t o cell d eat h. F o r i n sta n ce , p aclita x el-sta b iliz ed mic ro t ubu l es se r ve as a sca f f o l d f o r t h e b i nd i ng o f t h e d eat h -e f fect o r do mai n o f p r o - caspase - 8, and t h ere by e n a b li ng a cas p ase- 8 do w n stream pro te o l y ti c cascade . , T h i s cas p ase- 8–d e p e nd e n t mec h a n ism als o ser ves as a n im po rt an t bas i s f o r t he und ersta nd i ng o f t h e l o ss o f f un cti on a nd / o r l ow e xp r ess i on o f t he b r eas t c a n cer 1, earl y on set g e n e ( BRCA 1 ) ass o ciat ion w it h r es i s t ance t o ta x a n e t h era p y . Ano t h e r m echan i s m o f t he an tica n cer effect o f ta x a n es is c u rre n tl y b ei ng ela bor ate d and i s ti ed t o t he B -cell l y m pho ma- 2 (Bcl- 2 ) a n tia pop t o sis f amil y o f p r o t e i ns. P ac lit axe l h as b ee n s ho w n t o ca u se t h e pho s pho r y lati on of Bcl -2 and t he seques tr a ti o n o f Ba k a nd Bim; ho we v e r , t h is seemi ng l y ca n ce r - pr o t ec ti ve phospho r y lati on n ee d s t o b e rec on cile d a nd li k el y c orr elat es w it h Bc l- 2–exp r es si on le v els . I n teresti ng l y , n e u tralizi ng Bcl -2 ho m o l ogy 3 ( BH3 ) do mai n s wit h c o m pound s s u c h as AB T - 737 is s yn e r g is t i c w it h doce t axe l Cli n ical P ha rm aco l ogy Paclita xe l W it h pro l onged i n f us i on schedu les ( 6 a nd 24 hou rs) , d r ug d is po siti on is a b i ph asic p r ocess w it h va l ues f o r al ph a a nd b eta h alf-li v es a v era g i ng a pprox im a t e l y 20 mi nu t es and 6 hou rs , res p ecti v el y W h e n a d mi n istere d as a 3-h o u r i n f us i on, t he pha r m ac ok i n etics are non li n ear a nd ma y lea d t o un e xp ect ed t ox i c it y w it h a sm all do se escalati on, o r a d is p r opo rti on ate d ec r eas e i n d r ug exposu r e and l o ss o f t u m o r res pon se wit h a do se r e du cti on. App r ox im a t e l y 71 % o f a n a d mi n istere d do se o f p aclita x el is e x c r ete d i n t he s t oo l v i a t he en ter oh e p atic circ u lati on ov er 5 d a y s as eit he r t h e p a r ent co m pound o r m e t abo lites i n hu ma n s . Re n al cleara n ce o f p aclita x el and m e t abo lit es i s mi n imal , acc oun ti ng f o r 14 % o f t h e a d mi n is te r ed dose. I n hu m an s , t h e bu l k o f d r ug d is po siti on is meta bo liz ed by c y t och r o m e P- 450 mi xed -f un cti on ox i d ases — s p ecificall y , t h e

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is o e n z y m es CY P 2C8 and CYP3 A 4, w h ic h meta bo lize p aclita x el t o hydroxyla t ed 3′p - hyd r oxypac lita x el (mi no r) a nd 6α - hyd r oxyp aclita x el ( maj or), as we ll as d i hyd r oxy late d meta bo lites . N a nop arti c l e A l bu mi n - Bound Paclita x el N a b-p aclit axe l i s a so l ven t-free c o ll o i d al s u s p e n si on ma d e by ho m og e n i z i ng pac lit axe l w it h 3 % t o 4 % al bu mi n und er h i gh p ress u re t o for m n a nopa rti c l es o f ~130 n m t h at d is p erse i n p lasma t o ~ 10 n m (see ) . It r ece i ved r egu lat o r y a pp r ov al i n t h e U n ite d States i n 2005 b ase d on r esu lt s i n pa ti en t s w it h metastatic b reast ca n ce r , a nd is no w als o a pprov e d i n co m b i na ti on w it h car bop lati n f o r first-li n e treatme n t o f l o ca lly a dv a n ce d o r m e t as t a ti c N S CL C , a nd i n c o m b i n ati on wit h g emcita b i n e for f i r st - li ne tr ea tm en t o f m e t as t a tic p a n creatic a d e no carci no ma . T h e im prov e d r esponses seen w it h n a b - p aclita x el , w h e n c o m p are d t o s o l v e n t- b ase d pac lit axe l , a r e no t f u ll y und erst ood. Na b - p aclita x el li k el y ca p itali zes on se v er a l m echan i s m s, wh i ch i n cl ud e a n im p r ov e d ph armac ok i n etic prof ile wit h a l a r ge r vo l u m e o f d istri bu ti on a nd a h i gh er ma x imal c on ce n t ra ti on o f c ir cu l a ti ng, unbound, free d r ug ; im p r ov e d t u m o r acc u m ula ti on by t he enhanced p ermea b ilit y a nd rete n ti on (EPR) e f fect; and r ece p t o r -m ed i a t ed tr anscy t os i s v ia a n al bu mi n -s p ecific rece p t o r ( gp60 ) f o r e ndo t h e l i a l tr anscy t os i s and b i nd i ng o f secrete d p r o tei n aci d ic a nd ric h i n c y stei n e (S P ARC ) i n t he t u m o r i n terstiti u m I n c on trast t o c r em opho r/ e t hano l ( C rEL) so l v e n t- b ase d p aclita x el , n a b - p aclita x el e xh i bits a n e x ten s i ve ex tr avascu l a r vo l u me o f d istri bu ti on e x cee d i ng t h at o f wat e r , i nd icati ng ex t ens i ve ti ssue and e x tra v asc u lar p r o tei n d istri bu ti on. S o me st ud ies show t ha t nab - pac lit a xel ac h ie v es 33 % h i gh er d r ug c on ce n trati on ov e r C r EL- pac lit axe l Add i t i on all y , t h e ma x im u m c on ce n trati on (Cm ax ) , t h e mean p l as m a ha lf-lif e o f 15 t o 18 hou rs , t h e area und er c u r v e (AUC) , a nd t h e dose -i ndependen t p l a sma cleara n ce c o rres pond t o li n ear ph a r ma cok i ne ti cs ove r 80 t o 300 m g / m 2 T h e im p r ov e d d e po siti on o f a n a nop a r ti c l e, such as nab - pacl ita x el i n a t u m o r tiss u e , ca n o cc u r p assi v e ly t hrough an EP R e f f ec t i n a r ea s o f lea ky v asc u lat u re , s u f ficie n t v asc u lar p o r e size , a nd dec r eased l y m pha ti c fl o w O n ce i n t h e tiss u e , t h e n a b - p aclita x el nanoveh i c l e can de li v er t h e d r ug l o call y o r b e n efit fr o m f u rt he r r ece p t o r -m ed i a t ed t a r ge ti ng t o S P ARC , w h ic h h as b ee n s ho w n t o b e

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ov e r e xp r essed, and co rr e l a t es wit h d isease p r og ressi on i n ma ny t u m o r t yp es A lt hough p r ec li n ical m od els , as well as on e cli n ical trial , h a ve s hown how nanopa rti c l e t he ra py ca n b e n efit fr o m t h is tar g ete d a ppro ach co rr e l a ti ve da ta f o r n a b - p aclita x el is limite d. T h e h i gh st ro mal S P ARC l eve l was ass ociate d wit h l ong er s u r v i v al i n p atie n ts tre ated w it h n a b - pac lit axe l i n t he pha se I/II st udy o f p atie n ts wit h p a n creatic ca n ce r ; howeve r , t h i s co rr e l a t iv e a n al y sis was no t i n cl ud e d i n t h e ph ase III t r ial r e p ort and r equ ir es va li d ati on . Do ceta x el Th e ph arm acok i ne ti cs o f doc eta x el on a 1 - hou r sc h e du le is trie xpon e n ti al a nd li n e a r a t doses o f 1 15 m g /m 2 o r less . T ermi n al h alf-li v es ra ng i ng fr om 1 1.1 t o 18.5 hou r s has been r epo rte d. T h e m o st im po rta n t d etermi n a n ts o f do ceta x el c l ea r ance we r e t he body s u rface area (BSA) , h e p atic f un cti on, a nd p lasm a α 1 - ac i d g l ycop r o tei n c on ce n trati on. Plasma p r o tei n b i nd i ng i s h i gh (grea t e r t han 80 %) , and b i nd i ng is p rimaril y t o α 1 -aci d g l y c op r o tei n, al bu mi n, and li pop r o t e i ns. T he h e p atic c y t o c h r o me P- 450 mi x e d -f un cti on ox i d ase s, pa rti cu l a rl y i so f o rms CYP 3 A 4 a nd CYP 3 A 5, are p ri n ci p all y i nvo l v e d i n b i o tr ans f o rm a ti on. T h e p ri n ci p al ph armac ok i n etic d etermi nants of t ox icit y , pa rti cu l a rl y neu tro p e n ia , are d r ug e xpo s u re a nd t h e time t h at p lasma concen tr a ti ons exceed b i o l og icall y rele v a n t c on ce n trati on s . T h e b aseli n e l eve l o f α 1 - ac i d g l ycop r o tei n ma y b e ele v ate d as a n ac u te ph as e r eacta n t i n advanced d i sease a nd is a n i nd e p e nd e n t p re d ict o r o f res pon s e a nd a maj o r ob j ec ti ve p r ognos tic fact o r o f s u r v i v al i n p atie n ts wit h non– small - cell l ung cance r tr ea t ed wit h do ceta x el c h em o t h era p y . Ca b azit axe l Ca b azit axe l i s a se mi syn t he ti c d eri v ati v e o f t h e n at u ral ta xo i d 10 - d eacet y l bacca ti n III . It b i nds t o a nd sta b ilizes t h e β-t ubu li n s ubun it , r es u lti ng i n t he i nh i b iti on o f micr o t ubu le d e po l y merizati on a nd cell d i v isi on, ce ll cyc l e a rr es t i n t h e G 2 /M ph ase , a nd t h e i nh i b iti on o f t u m o r cell pro l i f e r a ti on . It i s ac ti ve a g ai n st d i v erse ca n cer cell li n es a nd t u m o r m od els tha t a r e sens iti ve and r esista n t t o do ceta x el , i n cl ud i ng p r o state , mammar y , m e l ano m a, k i dne y , c o l on, p a n creas , l ung, g astric , a nd h ea d an d

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n ec k. Cabaz it axe l i s a poo r sub strate f o r t h e mem b ra n e-ass o ciate d, m u lti drug r es i s t ance P- g l yco pr o tei n e f fl ux pu m p ; t h eref o re , is u sef u l f o r t r eati ng doce t axe l-r e fr ac t o r y p r o state ca n cer f o r w h ic h it g ai n e d FDA a pprov a l i n 2010. I n add iti on, it p e n etrates t h e b l ood–b rai n b arrie r .

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t h e clear ance r a t es o f doxo r ub ici n a nd doxo r ub ici no l w h e n doxo r ub ici n is a d mi n is te r ed a ft e r pac lit axe l . Se v eral a g e n ts t h at i nh i b it c y t o c h r o me P- 4 5 0 mi x e d-func ti on ox i dases i n t e rfere wit h t h e meta bo lism o f p aclita x el a nd do ceta x el i n hu m an mi c r osom es i n v itr o ; ho we v e r , t h e cli n ical rele v a n ce o f t h ese f in d i ngs i s no t known . T ox icit y Paclita xe l Th e mic e ll e -f o rmi ng C rEL v e h icle , w h ic h is re qu ire d f o r s u s p e n si on a n d i n t r a v e nous de li ve r y o f pac lita x el , ca u ses its non li n ear ph armac ok i n etic s a nd t h e reby im pac t s it s t he r ap e u tic i nd e x. CrEL ca u ses hyp erse n siti v it y r eacti ons, w it h m a j o r r eac ti on s u s u all y o cc u rri ng wit h i n t h e first 10 mi nutes a f te r t h e fir s t tr ea tm en t and res o l v i ng c o m p letel y after st opp i ng t h e t r eatme n t . A ll pa ti en t s shou l d b e p reme d icate d wit h ster o i d s , d i ph e nhyd r a mi ne, and an H2 an ta gon ist , alt hough up t o 3 % will still h a ve r eacti ons. T hose who have m a j o r reacti on s h a v e b ee n rec h alle ng e d s u ccess fu ll y a ft e r r ece i v i ng high do ses o f c o rtic o ster o i d s . N e uropa t hy i s t he p ri nc i pa l to x icit y o f p aclita x el . Paclita x el i ndu ces a p e r i ph e ra l neu r opa t hy t ha t p r e se n ts i n a s y mmetric st o c k i ng g l ov e d ist r i bu ti on, a t fir s t tr ans i en t and t h e n p ersiste n t . A n e u r o l og ic e x ami na ti on r evea l s senso r y l o ss , a nd n e u r ophy si o l og ic st ud ies re v eal a xon al degene r a ti on and de m y eli n ati on . C o m p are d wit h cis p lati n, a l oss of d ee p t endon r e fl exes occu rs less c o mm on l y ; ho we v e r , a u t ono mic a nd m o t or c hanges can occu r . S e vere n e u r o t ox icit y is un c o mm on w h e n p aclita x el i s g i ven a l one a t d oses b el o w 200 m g / m 2 on a 3 - o r 24 - hou r sc h e du l e eve r y 3 weeks, o r b el o w 100 m g / m 2 on a c on ti nuou s wee k l y sc h e du l e. T he r e i s no conv i n ci ng e v i d e n ce t h at a ny s p ecific meas u re is e f f ecti ve a t a m e li o r a ti ng ex i st i ng ma n ifestati on s o r p re v e n ti ng t h e d e v el opmen t o r wo r sen i ng o f n e u r o t ox icit y N e u t ropen i a i s a l so fr equen t wit h p aclita x el . T h e on set is u s u all y on d a y s 8 t o 1 1, a nd r ecove r y i s gene r a l ly c o m p lete by d a y s 15 t o 21 wit h a n e v ery 3 w ee k s dos i ng r eg im en. Neu tro p e n ia is non c u m u lati v e , a nd t h e du rati on o f se v e r e neu tr open i a—even i n h ea v il y p retreate d p atie n ts — is u s u all y b rie f.

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Se v e r it y o f neu tr open i a i s r e late d t o t h e du rati on o f e xpo s u re a bov e t h e b i o l og ic a ll y r e l evan t l eve l s o f 0.05 t o 0.10 μ M/L , a nd p aclita x el ’ s non li nea r ph a r ma cok i ne ti cs shou l d be con si d ere d w h e n e v er a d j u sti ng do se . Th e m o st co mm on ca r d i ac r hy t h m d ist u r b a n ce , a tra n sie n t si nu s br a dy ca rd i a, can be obse r ved i n up t o 30 % o f p atie n ts . R ou ti n e car d iac m on it oring du ri ng pac lit axe l t h era py is no t n ecessar y bu t is a dv isa b le f o r p atie n ts who m ay no t be ab l e t o t o lerate b ra dy arr hy t h mias . Dr ug -relate d g ast ro i n t es ti na l e f f ec t s, such as vo miti ng a nd d iarr h ea , are un c o mm on. Se v e r e hepa t o t ox i c it y and pan creatitis h a v e als o b ee n no te d rarel y . P u lm ona r y t ox i c iti es, i nc l ud i ng ac u te b ilateral pn e u m on itis , h a v e b ee n r e por te d. E x tr avasa ti on o f l a r g e vo l u mes ca n ca u se m od erate s o ft tiss u e i n j ur y . P ac lit axe l a l so i nduce s re v ersi b le al op ecia o f t h e scal p i n a do se- r elate d f a sh i on. Na il d i so r de rs h a v e als o b ee n re po rte d wit h p aclita x el use a nd i n cl ude ri dg i ng, na il bed p i g me n tati on, ony c ho rr h e x is , a nd ony c ho l ys i s. T hese s i de e f f ec ts h a v e b ee n re po rte d m o re c o mm on l y wit h do se - i n te ns ifi ed pac lit axe l r eg ime n s . Rece n t s t ud i es have sugges t e d a r o le f o r t h e a d e no si n e tri pho s ph atase ( A TP)-b i nd i ng casse tt e ( ABC ) tra n s po rter po l y m o r ph isms i n t h e d e v el opmen t o f neu r opa t hy a n d n e u tr op e n ia . Siss ung et al . re po rte d t hat p atie n ts ca rr y i ng t wo r e f e r en ce alleles f o r t h e ABCB 1 (P- g l y c op r o tei n, M D R 1) 3435C g r ea t e r t han T po l y m o r ph ism h a d a re du ce d ris k t o d e v e lop n e urop a thy as co m pa r ed t o pa tie n ts carr y i ng at least on e v aria n t allele ( P = .09). D at a fr o m a l a r ge con tr o lle d trial t o e v al u ate t h ese a nd o t h er ca nd i date po l y m o r ph i s m s f a il ed t o de t e ct a si gn ifica n t ass o ciati on b etwee n g e no t ype a nd ou t co m e o r t ox i c it y f o r any o f t h e g e n es a n al y ze d, alt hough t h e c orr elati ve s t ud i es we r e r e tr o s p ecti v e a nd t h e sam p le size was i n a d e qu ate to ru le ou t s m a ll e r d i f f e r ences. A la r g e ra ndo mize d trial o f t h e CALGB 40101 us i ng an i n t eg r a t ed geno mewi d e ass o ciate st udy f ound tw o po l y m o r ph i s m s assoc i a t ed w it h p aclita x el-i ndu ce d po l yn e u r op at h y B oth a r e i nvo l ved i n ne r ve deve l op me n t a nd mai n te n a n ce , i n cl ud i ng t h e h e r e d ita ry pe ri phe r a l neu r opa t hy C h arc o t-Marie- T oo t h d isease g e n e , F GD4. F u rt he r s t ud i es a r e r equ ire d t o a d e qu atel y assess t h e r o le o f t h ese v a r ia n ts i n p r ed i c ti ng t ox i c it y fr o m ta x a n e t h era p y . N a b-p aclit axe l

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Hyp e r se ns iti v it y r eac ti ons hav e no t b ee n ob ser v e d du ri ng t h e i n f u si on p e r i od a nd, t he r e f o r e, s t e r o i d p reme d icati on s are no t n ecessar y . T h e mai n do se - limiti ng t ox i c iti es a r e neu tr op e n ia a nd se n s o r y n e u r op at h y . I n a tria l c o m p a r i ng week l y pac lit axe l 90 m g / m 2 t o n a b - p aclita x el 150 m g / m 2 t o i x a b e p il one i n pa ti en t s w it h metastatic b reast ca n ce r , t h ere was m o re h emat o l og i c t ox i c it y and pe ri ph eral n e u r op at hy i n t h e n a b - p aclita x el ar m c o m p a red t o t he pac lit axe l a r m, alt hough me d ia n p r og ressi on -free s u r v i val w as no t si gn ifi can tl y d i f f e r en t at t h e 12 -m on t h f o ll o w- up . T h is le d t o do se r e duc ti ons i n 45 % o f pa tie n ts i n t h e n a b - p aclita x el arm c o m p are d w ith 15% for t he pac lit axe l a rm Ot h er t ox icities i n cl ud e al op ecia , d iarr h ea, n a u sea and vo miti ng, e l eva ti on s i n li v er e n z y mes , art h ral g ia , m y al g ia , a nd ast h e n ia . Do ceta x el N e u t ropen i a i s t he m a i n t ox i ci t y o f do ceta x el . W h e n do ceta x el is a d mi n is te r ed on an eve r y 3 w ee k s sc h e du le , t h e on set o f n e u tr op e n ia is u s u all y no t ed on day 8, w it h co m p lete res o l u ti on by d a y s 15 t o 21. N e u t ropen i a i s s i gn ifi can tl y l e ss w h e n l o w do ses are a d mi n istere d wee kl y . F DA b l ack box wa r n i ngs i nc lu d e i n crease d t ox icit y i n p atie n ts wit h a bnor m a l li ve r f unc ti on and, i n select NSCLC p atie n ts t h at recei v e d p ri o r p lati nu m , seve r e hype r sens iti v it y reacti on s a nd se v ere fl u i d rete n ti on d es p ite dexa m e t hasone a t- hom e p reme d icati on. Hyp e r se ns iti v it y r eac ti ons w ere no te d i n a pp r ox imatel y 31 % o f p atie n ts who r ecei ved t he d r ug w it hou t p reme d icati on s i n earl y st ud ies . S y m p t oms i n cl ud e fl ush i ng, r ash, ches t ti gh t n ess , b ac k p ai n, dy s pn ea , a nd fe v er o r c h ills . Seve r e hypo t ens i on, b r on c ho s p asm , g e n eralize d ras h, a nd er y t h em a ma y als o occu r . Ma j o r r eac ti on s u s u all y o cc u r du ri ng t h e first tw o c our ses and w it h i n mi nu t es a fter t h e start o f treatme n t . Si gn s a nd s y m p t oms g e n e r ally r eso l ve w it h i n 15 mi nu tes after cessati on o f treatme n t , a nd do ceta x el can usua ll y be r e i ns tit u te d wit hou t se qu elae after treatme n t wit h d i ph e nhyd r a mi ne and an H2 -rece p t o r a n ta gon ist . D o ceta x el i ndu ces a un i qu e f l u i d r e t en ti on synd r o me c h aracterize d by e d ema , wei gh t g ai n, a nd t h i rd- s p a ce fl u i d co ll ec ti on. F lu i d rete n ti on is c u m u lati v e a nd is du e t o i n c r ease d cap ill a r y pe rm eab il i t y . Pr ophy lactic treatme n t wit h

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c or tic o st e r o i ds has been de mo n strate d t o re du ce t h e i n ci d e n ce o f fl u i d r ete n ti on. Agg r ess i ve and ea rl y treatme n t wit h d i u retics h as b ee n s u ccess fu ll y used t o m anage fl u i d rete n ti on. S k i n t ox icit y ma y o cc u r i n as ma ny as 50 % t o 75 % o f pa ti en ts; ho we v e r , p reme d icati on ma y re du ce t he ov e r all in c i dence o f t h i s e f f ec t . Ot h er c u ta n e ou s e f fects i n cl ud e p almar – p la n ta r e r y t h r odyses t hes i a and ony c hody str oph y . D o ceta x el p r odu ces n e uro t ox i c it y , wh i ch i s qua litati v el y similar t o t h at o f p aclita x el; ho we v e r , n e uro se nso r y and neu r o m uscu lar e f fects are g e n erall y less fre qu e n t a nd less se v e r e t han w it h pac lit axe l . M il d -t o -m od erate p eri ph eral n e u r o t ox icit y o cc ur s in app r ox im a t e l y 40 % o f un treate d p atie n ts . Ast h e n ia h as b ee n a pro mi n e n t co m p l a i n t i n pa ti e nts w ho h a v e b ee n treate d wit h la r g e c u m u lati ve doses. St o m a titi s a pp ears t o o cc u r m o re fre qu e n tl y wit h do ceta x el t han w it h pac lit axel. Ot h er re po rte d t ox icities o f no te i n cl ud e n ec ro tiz ing en t e r oco liti s, i n t er stitial pn e u m on itis , a nd o r g a n izi ng pn e u m on i a. Ca b azit axe l A ph ase III m u lti-i ns tit u ti ona l st udy o f me n wit h metastatic castrati on - r esista n t p r os t a t e cance r who h a d faile d do ceta x el im p r ov e d ov erall me dian s urv i v al on cabaz it axe l co m p are d t o mit ox a n tr on e Ca b azita x el was a pprov e d by t he F DA i n June 2010 t o treat metastatic castrati on -resista nt pro state cance r i n t hose who h a d recei v e d p ri o r c h em o t h era p y . T h is was d es p ite a h i ghe r r a t e o f adve rse d eat h s ( 4.9 %) , a t h ir d o f w h ic h were du e to n e u t ropen i c seps i s. Cabaz it axe l was ass o ciate d wit h m o re g ra d e 3 o r 4 n e u t ropen i a ( 82 %) t han mit ox a n tr on e ( 58 %) . Si d e e f fects re po rte d i n m o r e t h a n 20 % o f pa ti en t s tr ea t ed w it h ca b azita x el i n cl ud e d m y el o s upp ressi on, d ia rrh ea , nausea, vo miti ng, con sti p ati on, a bdo mi n al p ai n, o r ast h e n ia . F DA b lac k box wa r n i ngs a r e s imil a r t o t ho se f o r do ceta x el . VIN C A A L KA L O I D S Th e v i n c a a l ka l o i ds have been s o me o f t h e m o st acti v e a g e n ts i n ca n cer c h em o t he r apy s i nce t he ir i n tr odu cti on 40 y ears a go. T h e n at u rall y o cc urr i ng m e m be r s o f t he f am il y , v i nb lasti n e (VBL) a nd v i n cristi n e (VCR) , w e r e is o l a t ed fr o m t he l eaves o f t h e p eriwi nk le p la n t Cat h ara n t hu s r o se us G. Don. I n t he l a t e 1950s, t he ir a n timit o tic a nd, t h eref o re , ca n cer

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c h em o t he r apeu ti c po t en ti a l w as d isc ov ere d by g r oup s bo t h at Eli Lill y Resea r c h L abo r a t o ri es and a t t h e U n i v ersit y o f W ester n O n tari o, a nd t h e y came i nto w i desp r ead use f o r t h e si ng le-a g e n t treatme n t o f c h il dhood h emat o l og i c and so li d m a li gn a n cies a nd, s ho rtl y afte r , f o r a du lt h emat o l og i c m a li gnanc i es ( s ee T h eir cli n ical e f ficac y i n se v e r al co m b i na ti on t he r ap i e s h as le d t o t h e d e v el op me n t o f v ari ou s novel semis yn t he ti c ana l ogs, i nc l ud i ng v i no rel b i n e (VRL) , v i nd esi n e (VDS) , a nd v i nf l un i ne ( V FL) . Mec h a n i s m o f Ac ti on In c on t r a s t t o t he t axanes, t he v i n ca al k al o i d s d e po l y merize micr o t ubu les a nd d estr oy mit o ti c sp i nd l es . At l o w bu t cli n icall y rele v a n t c on ce n trati ons, V B L does no t depo l y m e ri ze sp i nd le micr o t ubu les , y et it po werf u ll y b l ocks mit o sis . T h i s has been sugges te d t o o cc u r as a res u lt o f t h e s upp ressi on o f mic ro t ubu l e dyna mi cs r a t he r t h a n micr o t ubu le d e po l y merizati on. T h is group of co m pounds b i nds t o t h e β s ubun it o f t ubu li n d imers at a d isti n c t r e g i on c a ll ed t he v i nca - b i nd i ng do mai n. Im po rta n tl y , VBL b i nd i ng i ndu c es a c onforma ti ona l change i n t ubu li n i n c onn ecti on wit h t ubu li n self-ass o ciat ion. I n mit o ti c sp i nd l e s , t h e sl o wi ng o f t h e g r o wt h a nd s ho rte n i ng or t r ea d milli ng dyna mi cs o f t h e micr o t ubu les b l o c k mit o tic p r og ressi on. D is rup ti on o f t he no rm a l mit o tic s p i nd le assem b l y lea d s t o d ela y e d cell c y cle pr o g r ess w it h ch r o m os omes st u c k at t h e s p i nd le po les a nd un a b le to p ass from m e t aphase i n t o ana p h ase , w h ic h e v e n t u all y i ndu ces t o a pop t osis. Th e n at u r a ll y occu rri ng v i nca al k al o i d s VCR a nd VBL , t h e semis yn t h et ic a n al og V R L , and a nove l b ifl uo ri n ate d a n al og VFL h a v e similar mec h a nis m s o f ac ti on. T iss u e an d t u m o r sens iti v iti e s t o t h e v i n ca al k al o i d s , w h ic h, i n p art , relat e t o d i f f e rences i n d r ug tr anspo rt a nd acc u m u lati on, als o v ar y . I n tracell u lar o r e x t r acel lu l a r concen tr a ti on r a ti o s ra ng e fr o m fi v e- t o 500 -f o l d d e p e nd i ng on t h e i nd i v i dua l ce ll t ype, li pop hilicit y , tiss u e-s p ecific fact o rs s u c h as t ubulin is o t yp e c o m pos iti on, and ti ssu e-s p ecific micr o t ubu le-ass o ciate d p r o tei ns ( M A P ). – A lt hough t he v inca al k al o i d s are retai n e d i n cells f o r l ong p e r i od s o f tim e and t hus m ay h a v e p r o l ong e d cell u lar effects , i n tracell u l a r r ete n ti on i s m a r ked l y d i f f e r en t am ong t h e v ari ou s v i n ca al k al o i d s . F o r i n sta n ce , VB L appea r s t o be r etai n e d i n li poph ilic tiss u e m u c h m o re t h a n

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eit h e r VCR o r VD S Newe r t h e o ries o f a n timicr o t ubu le a g e n ts’ mec h a nis m o f ac ti on have e me r g e d, s ugg esti ng t h at t h e m o re im po rta n t ta r g et o f t hese d r ugs m ay be t h e t u m o r v asc u lat u re , as re v iewe d i n t h e n e xt secti on. Cli n ical P ha rm aco l ogy Th e v i n c a a l ka l o i ds a r e usua ll y a d mi n istere d i n tra v e nou sl y as a b rief i nfu si on, and t he ir pha rm acok i n etic b e h a v i o r i n p lasma h as g e n erall y b e en e xp lai ned by a t h r ee - co m pa rt m e n t m od el . T h e v i n ca al k al o i d s s h are ma ny ph a r ma cok i ne ti c p r ope rti es, i n cl ud i ng lar g e vo l u mes o f d istri bu ti on, h i gh clea r a n c e r a t es, and l ong t e rmi n al h alf-li v es t h at reflect t h e h i gh ma gn it ude a nd a v i d it y o f d r ug b i nd i ng i n p eri ph eral tiss u es . VCR h as t h e l ong est te r mi n al ha lf-lif e and t he l ow est cleara n ce rate; VBL h as t h e s ho rtest te r mi n al ha lf-lif e and t he h i gh est cleara n ce rate; a nd VDS h as i n terme d i ate c h a r acteri s ti cs. A lt hough p r o l ong e d i n f u si on sc h e du les ma y a vo i d e x cessi ve l y t ox i c peak concen trati on s a nd i n crease t h e du rati on o f d r ug e xpo s ure i n p l as m a above b i o l og icall y rele v a n t t h res ho l d c on ce n trati on s , t h e r e is littl e ev i dence t o suppo rt t h e no ti on t h at p r o l ong e d i n f u si on s are m or e e f f ec ti ve t han bo l us schedu les . T h e l ong est h alf-life a nd l o west clea r a n c e r a t e o f VCR m ay ac c oun t f o r its g reater p r op e n sit y t o i ndu ce n e uro t ox i c it y , bu t t he r e a r e m any o t h er nonph armac ok i n etic d etermi n a nts of tiss ue sens iti v it y , as d i scuss e d i n t h e p re v i ou s secti on. V i n c r isti ne Af te r c onven ti ona l doses o f VCR ( 1.4 m g / m 2 ) g i v e n as b rief i n f u si on s , p ea k p la s m a l eve l s app r oach 0.4 μ m o l . Plasma cleara n ce is sl o w , a nd te r mi n al ha lf-li ves t ha t r ange fr o m 23 t o 85 hou rs h a v e b ee n re po rte d. VCR is metab o li zed and exc r e t ed p rimaril y by t h e h e p at ob iliar y s y stem . T h e n at ur e o f t he VCR m e t abo lit e s i d e n tifie d t o d ate , as well as t h e res u lts o f meta bo li c s t ud i es i n v itr o, i nd icate t h at VCR meta bo lism is me d iate d pr i n ci p all y by hepa ti c cy t och r o me P- 450 CYP 3 A 5. V i nb last ine

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Th e cli n i ca l pha rm aco l ogy o f VBL is similar t o t h at o f VCR . VBL b i nding t o p las ma p r o t e i ns and f o rm ed eleme n ts o f b l ood is e x te n si v e Pea k p lasma d r ug concen tr a ti ons ar e a pp r ox imatel y 0.4 μ m after ra p i d i n t r a v e nous i n j ec ti ons o f VBL at sta nd ar d do ses . Distri bu ti on is ra p i d, a nd te r mi n al ha lf-li ves r ange fr o m 20 t o 24 hou rs . Li k e VCR , VBL d is po siti on is pr i n ci pa ll y t h r ough t he hep at ob iliar y s y stem wit h e x creti on i n feces ( a pproxi m a t e l y 95 %); howev e r , fecal e x creti on o f t h e p are n t c o m pound is l o w , i nd i ca ti ng t ha t hepa ti c meta bo lism is e x te n si v e . V i nor el b i ne Th e ph arm aco l og i c behav i o r o f VRL is similar t o t h at o f t h e o t h er v i n ca al k al o i ds, and p l as m a concent rati on s after ra p i d i n tra v e nou s a d mi n istrat ion h a v e b e en r epo rt ed t o dec li ne i n eit h er a b ie xpon e n tial o r trie xpon e n tial ma nn e r . A ft e r i n tr avenous a d mi n istrati on, t h ere is a ra p i d d eca y o f VR L c on ce n t ra ti ons f o ll owed by a m u c h sl o wer elimi n ati on ph ase (termi n al hal f-li f e , 18 t o 49 hou r s ) . Pl as m a p r o tei n b i nd i ng, p ri n ci p all y t o α 1 -aci d g l y c opro t e i n, a l bu mi n, and li pop r o tei n s , h as b ee n re po rte d t o ra ng e fr o m 80% t o 91 % , and d r ug b i nd i ng t o p latelets is e x te n si v e . VRL is wi d el y d ist r i bu t ed, and h i gh concen t r ati on s are f ound i n v irt u all y all tiss u es , e x c ept t h e ce n t ra l ne r vous sys t e m . T h e wi d e d istri bu ti on o f VRL reflects its li poph il ic it y , wh i ch i s a m ong t h e h i gh est o f t h e v i n ca al k al o i d s . As wit h o t h e r v i nca a l ka l o i ds, t he li ver is t h e p ri n ci p al e x cret o r y o r g a n, a nd up t o 80% of V R L i s exc r e t ed i n t h e feces , w h ereas u ri n ar y e x creti on re p rese nts on l y 16 % t o 30 % o f t o t a l d r ug d is po siti on, t h e bu l k o f w h ic h is un meta bo li zed VR L . St ud i es i n hu ma n s i nd icate t h at 4 -O- d eacet y l-VRL a nd 3,6-epoxy - VR L a r e t he pr i n ci p al meta bo lites , a nd se v eral mi no r hydroxy-VR L i so m e r m e t abo lites h a v e b ee n i d e n tifie d. Alt hough m o st meta bo lit es a r e i nac ti ve, t he deacet y l-VRL meta bo lite ma y b e as acti v e a s V R L. T h e cy t och r o m e P- 450 CYP 3 A is o e n z y me a pp ears t o b e p ri n ci p al ly i nvo l v e d i n b i o tr ans f o rm a ti on. V i nf l un i ne V F L is a nove l se mi syn t he ti c micr o t ubu le i nh i b it o r wit h a fl uo ri n ate d cat h a r a n t h i ne m o i e t y , wh i ch t r a n slates i n t o l o wer a f fi n it y f o r t h e v i n ca b i nd i ng s it e on t ubu li n and, t h eref o re , d i f fere n t qu a n titati v e e f fects on

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mic ro t ubu l e dyna mi cs T he l o w a f fi n it y f o r t ubu li n ma y b e res pon si b l e for its r e duced c li n i ca l neu r o t ox icit y . Des p ite t h is l o wer a f fi n it y , it is m o r e acti v e in v i vo t han o t he r v i nca al k al o i d s , a nd resista n ce d e v el op s m o re sl ow l y . V FL i s a new v i nca and still und er cli n ical d e v el op me n t . Its vo l ume of d ist r i bu ti on i s l a r ge, and h as a termi n al h alf-life o f n earl y 40 hou rs

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Th e on l y ac ti ve m e t abo lit e i s 4 -O- d eacet y l v i n fl un i n e , w h ic h h as a termi nal h al f- li f e app r ox im a t e l y 5 days l ong er t h a n t h at o f t h e p are n t c o m pound . Drug In t e r ac ti ons Met ho t rexa t e accu m u l a ti on i n t u m o r cells is e nh a n ce d i n v itr o by t h e pr ese n c e o f VCR o r VB L , an e f fect me d iate d by a v i n ca al k al o i d– i ndu ce d b l o c k a d e o f d r ug e f fl ux ; howev e r , t h e mi n imal c on ce n trati on s o f VCR r e qu i r e d t o ach i eve t h i s e f f ec t o cc u r on l y tra n sie n tl y i n v i vo . T h e v i n c a al k al o i ds a l so i nh i b it t he ce ll u lar i n fl ux o f t h e e p i podophy ll o t ox i n s i n v i t r o, r es u lti ng i n l ess cy t o t ox i c it y . H o we v e r , t h e cli n ical im p licati on s o f t h is po te n tial i n t e r ac ti on a r e unkno w n. L-as p ara g i n ase ma y re du ce t h e h e p at ic clea r a n c e o f t he v i nca a l ka l o i d s , w h ic h ma y res u lt i n i n crease d v i n ca- r elate d t ox i c it y . T o mi n imi ze t h e po ssi b ilit y o f t h is i n teracti on, t h e v i n ca al k al o i ds shou l d be g i ven 12 t o 24 hou rs b ef o re L-as p ara g i n ase . T h e c o m b i ned use o f mit o m yc i n C a nd t h e v i n ca al k al o i d s h as b ee n ass o ciate d w it h acut e dyspnea and b r on c ho s p asm . T h e on set o f t h ese pu lm on ar y t ox icitie s has r anged fr o m w i th i n mi nu tes t o hou rs after treatme n t wit h t he v i n ca alk a l o i ds, o r up t o 2 we e k s after mit o m y ci n C . T r eatment w it h t he v i nca a l k al o i d s h as p reci p itate d seiz u res ass o ciate d with s ub t h e r a peu ti c p l as m a pheny t o i n c on ce n trati on s . Re du ce d p lasma ph e ny t o i n l eve l s have been no te d fr o m 24 hou rs t o 10 d a y s after treatme nt w it h VCR and VB L . Because o f t h e im po rta n ce o f t h e c y t o c h r o me P- 45 0 C YP3A i soenzy m e i n v i nca alk al o i d meta bo lism , a d mi n istrati on o f t h e v i n ca alk a l o i ds w it h e r y t h r o m y ci n a nd o t h er i nh i b it o rs o f CYP 3 A ma y l ead t o se v e re t ox i c it y Conco mi t a n tl y a d mi n istere d d r ug s , s u c h as p e n t ob a rb it a l and H 2 -r ecep t or a n ta gon ists , ma y als o i n fl u e n ce VCR clea r a n c e by m odu l a ti ng hepa tic c y t o c h r o me P- 450 meta bo lic p r o cesses . T ox icit y

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D es p ite c l ose s imil a riti es i n s tr u ct u re , t h e v i n ca al k al o i d s d i f fer i n t h eir sa f et y p r o fil es. Neu tr open i a is t h e p ri n ci p al do se-limiti ng t ox icit y o f VB L a nd V R L. T h r o m bocy t open i a a nd a n emia o cc u r less c o mm on l y . T h e onset of n e u t ropen i a i s usua ll y day 7 t o 1 1, wit h rec ov er y by d a y 14 t o 21, a nd ca n b e po t en ti a t ed by hepa ti c dy sf un cti on. Gastr o i n testi n al a u t ono mic dy s fun c t i on, as m an if es t ed by b l o ati ng, c on sti p ati on, ile u s , a nd a bdo mi n a l p ai n, o cc u r m os t co mm on l y w it h VCR o r h i gh do ses o f t h e o t h er v i n ca al k al o i ds. Mucos iti s occu r s mo re fre qu e n tl y wit h VBL t h a n wit h VRL a nd is least co mm on w it h VCR. N a u sea , vo miti ng, d iarr h ea , a nd p a n c r eatiti a l so occu r t o a lesser e x te n t . V CR pr i nc i pa ll y i nduces neuro t ox icit y c h aracterize d by a p eri ph eral , s y mmet r i c mi xed senso r y m oto r a nd a u t ono mic po l yn e u r op at h y . , T oxic ma n i f est a ti ons i nc l ude cons ti p ati on, a bdo mi n al cram p s , p aral y tic ile u s , ur i n a ry re t en ti on, o rt hos t a ti c h ypo te n si on, a nd hyp erte n si on. Its p rimar y n e urop a tho l og i c e f f ec t s a r e du e t o i n terfere n ce wit h a xon al micr o t ubu le fun cti on. E a rl y sy mm e tri c sen s o r y im p airme n t a nd p arest h esias ca n progr es s t o neu riti c pa i n and lo ss o f d ee p te ndon refle x es wit h c on ti nu ed t r eatme n t , wh i ch m ay be f o ll o we d by f oo t d r op, wrist d r op, m o t o r dy s fun c t i on, a t ax i a, and pa r a l y sis . Cra n ial n er v es are rarel y a f fecte d b eca u se t he up t ake o f VCR int o t h e ce n tral n er vou s s y stem is l o w . Se v e re n e uro t ox i c it y occu r s i n fr equen tl y wit h VBL a nd VDS . VRL h as b ee n s hown t o have a l owe r a f fi n it y f o r a xon al micr o t ubu les t h a n eit h er VCR o r V B L, wh i ch see m s t o be conf irme d by cli n ical ob ser v ati on s . Mil d -t o -m od e r at e pe ri phe r a l neu r opa t h y , p ri n ci p all y c h aracterize d by se n s o r y e f f ects , occu r s i n 7 % t o 31 % o f p atie n ts , a nd c on sti p ati on a nd o t h er a u t ono mi c e f f ec t s a r e no t ed i n 30 % o f p atie n ts , w h ereas se v ere t ox icit y o cc ur s in 2 % t o 3 % . In a du lt s, neu r o t ox i c it y m ay o cc u r after treatme n t wit h c u m u lati v e do se s as little as 5 t o 6 m g, and m an ifestati on s ma y b e p r o f ound after c u m u lati v e do ses of 15 t o 20 m g. P a ti en ts wit h d ela y e d b iliar y e x creti on o r h e p atic dy s fun c t i on, and t hose w it h an tece d e n t n e u r o l og ic d is o r d ers , s u c h as C h a r c o t -Ma ri e - T oo t h d i sease , h ere d itar y a nd se n s o r y n e u r op at hy t yp e 1, a nd Gu ill a i n - Ba rr é synd r o m e, are p re d is po se d t o n e u r o t ox icit y .

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Th e v i n c a a l ka l o i ds a r e po t en t v esica n ts . T o d ecrease t h e ris k o f ph le b iti s, t h e v ei n shou l d be adequa t e l y fl u s h e d after treatme n t . If e x tra v asati on is s u s p ecte d, tr ea tm en t shou l d b e d isc on ti nu e d, as p irati on o f a ny resi du al d r ug r emai n i ng i n t he ti ssues should b e attem p te d, a nd p r o m p t a pp licati on o f h eat (no t i ce ) f o r 1 hou r f ou r times d ail y f o r 3 t o 5 d a y s ca n limit tiss u e d ama g e Hya l u r on i dase, 150 t o 1,500 U ( 15 U/mL i n 6 mL 0.9 % s od iu m c h l or i d e so l u ti on ) subcu t aneou sl y , t h r ough si x cl o c k wise i n jecti on s i n a ci r c u m f er en ti a l m anne r us i ng a 25 - g a ug e n ee d le (c h a ng i ng t h e n ee d le wi th eac h n e w i n j ec ti on ) i n t o t he su rr ound i ng tiss u es ma y mi n imize d isc o mf o r t a nd latent ce ll u liti s. A su r g i c al c on s u ltati on t o c on si d er earl y d e b ri d eme nt is als o r e co mm ended. M il d and re v ersi b le al op ecia o cc u rs i n a pp r ox ima tely 10% a nd 20 % o f pa ti en t s tr eat e d wit h VLR a nd VCR , res p ecti v el y . Ac ute ca rd iac i sche mi a, ches t pa i ns w it hou t e v i d e n ce o f isc h emia , fe v e r , Ra ynaud s yndro m e, hand– f oo t synd r o me , a nd pu lm on ar y a nd li v er t ox icit y ( t r a n sami n iti s and hype r b ilir ub i n emia) h a v e als o b ee n re po rte d wit h u se o f t h e v i n c a a l ka l o i ds. A ll o f t he v i n ca al k al o i d s ca n ca u se a s ynd r o me o f i n a pprop ri a t e sec r e ti on o f an t id i u retic ho rm on e (SIADH) , a nd p atie n ts who a r e r ece iv i ng i n t ens i ve hyd r a t ion are p artic u larl y p r on e t o se v ere hypon atr e mi a seconda r y t o SIADH . M I CR O T UBU LE AN T AGON ISTS E st r am us ti ne P hospha t e E st r am us ti ne i s a con j uga t e of no r - n itr og e n m u star d li nk e d t o 17 β-estra diol by a ca rba m a t e es t e r b ri dge. Estram u sti n e pho s ph ate recei v e d re gu lat o r y a pprov a l i n t he Un it ed St a t es i n 1981 f o r treati ng p atie n ts wit h castrati on - r esista n t p r os t a t e cance r ( CRP C) . Alt hough t h e rec o mme nd e d d ail y do se o f est r am us ti ne phospha t e i s 14 m g / kg p er d a y , p atie n ts are u s u all y treate d in t h e d ail y dos i ng r ange o f 10 to 16 m g / kg i n t h ree t o f ou r d i v i d e d d ail y do ses ( s ee . E s tr a m u sti n e h as si gn ifica n t acti v it y i n CRPC a nd h a d b ee n used i n co m b i na ti on wit h VBL o r do ceta x el . H o we v e r , ph ase III t r ials i n pa ti en t s w it h CR P C sho we d t h at w h e n c o m b i n e d wit h do ceta x el , t h e r e is no added bene fit t o ov erall s u r v i v al c o m p are d t o do ceta x el al on e

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E st r am us ti ne b i nds t o β-t ubu li n at a site d isti n ct fr o m t h e c o lc h ici n e a nd v i n ca alk a l o i d b i nd i ng s it es. T h is a g e n t d e po l y merizes micr o t ubu les a nd mic rof il a m en t s, b i nds t o and disr up ts MAPs , a nd i nh i b its cell g r o wt h at h i gh c oncen tr a ti ons, r esu lti ng i n mit o tic arrest a nd a pop t o sis i n t u m o r c ells. Th e sele c ti ve accu m u l a ti on a n d acti on s o f estram u sti n e pho s ph ate a nd it s meta bo lit e, es tr o m us ti ne, i n sp ecific tiss u es a pp ear t o b e d e p e nd e n t on th e e xpr essi on o f t he es tr a m us ti n e- b i nd i ng p r o tei n (EMBP) . T h e d is po siti on o f est r am us ti ne i s p ri nc i pa ll y by ra p i d ox i d ati v e meta bo lism o f t h e p are n t c o m pound t o es tr o m us ti ne. E s tr o m u sti n e c on ce n trati on s i n p lasma are ma x imal w it h i n 2 t o 4 hou r s after o ral a d mi n istrati on, a nd t h e mea n elimi n ati on ha lf-lif e o f es tr o m u sti n e is 14 hou rs . Estr o m u sti n e a nd est r am us ti ne a r e p ri nc i pa ll y ex crete d i n t h e feces , wit h on l y small am ounts of c on j uga t ed es tr one and es tra d i o l d etecte d i n t h e u ri n e (less t h a n 1 %) . In g e n e ra l , t h i s agen t has a ma n a g ea b le safet y p r o file . Na u sea a nd vo mi ting a r e t h e pri nc i pa l t ox i c iti es en c oun tere d. I n c on trast t o t h e ta x a n es a nd t h e v i n ca alk a l o i ds, m ye l osupp r e ssi on is rarel y cli n icall y rele v a n t . C o mm on est rog e n i c s i de e f f ec t s i nc l ud e gyn ec o mastia , n i pp le te nd er n ess , a nd fl u i d r ete n ti on. T h r o m boe m bo li c co m p licati on s ma y o cc u r i n up t o 10 % o f p atie n ts. Epo t h ilo nes Th e e po t h il ones a r e m ac r o li d e c o m pound s t h at were i n itiall y is o late d fr om t h e m y c obac t e ri u m S o r ang i um cell u l o s u m . T h e y e x ert t h eir c y t o t ox ic e f f ects by p r o m o ti ng t ubu li n p o l y merizati on a nd i ndu ci ng mit o tic arrest .

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In g e n e ra l , t he epo t h il ones a re m o re po te n t t h a n t h e ta x a n es . I n c on trast to t h e ta x an es and v i nca a l ka l o i d s , ov ere xp ressi on o f t h e effl ux p r o tei n P- g l y c opro t e i n mi n im a ll y a f f ec ts t h e c y t o t ox icit y o f e po t h il on es . E po t h il o n es i n cl ud e t he na t u r a l epo t h il on e B ( p at up il on e; EPO 906 ) a nd se v eral semis yn t he ti c epo t h il one compound s s u c h as aza-e po t h il on e B ( i x a b e p il one ; BM S- 247550 ) , epo t h il on e D ( d e oxy e po t h il on e B , KOS- 862 ) , a nd a fu ll y syn t he ti c ana l og, s a gop il on e (ZK-EPO) . Ix a b e p il one has been eva l ua te d i n se v eral sc h e du les u si ng a crem opho r - b ase d f orm u l a ti on and i s F D A a pp r ov e d f o r t h e treatme n t o f p atie n ts wit h br east c ance r . It i s ac ti ve i n b reast ca n cer p re v i ou sl y treate d wit h

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Th e r e do no t appea r t o be ac t iv e meta bo lites on ce t h e p are n t d r ug is hydro l yzed, wh i ch i s t he m a i n elimi n ati on p at h wa y Ma y ta ns i no i ds and Au ri s t a ti n s: DM 1, MMAE An ti body d r ug con j uga t es ( A DC) were first attem p te d wit h d eli v er y o f doxorubic i n. A lt hough ti ssue l o calizati on seeme d p r o misi ng, it b ecame clea r t ha t t he de li ve r y o f m o r e po te n t c h em o t h era p e u tics was n ecessar y One o f t he maj o r a dv a n ces f o r t h e p r o mise o f ADC cam e w it h t h e d i scove r y and deve lo p me n t o f h i gh l y po te n t a n tica n cer c o m pounds s u c h as c a li chea mi c i ns, m ay t an si no i d s , a nd a u ristati n s . T h e n e x t n ecessar y advance was a li nk er t h at release d t h e d r ug on l y w h e n i n te nded, a nd a void i ng, o r i n so m e case s ca p italizi ng on, i n v i vo p r o teases , ox i d izi ng, or r e du ci ng env ir on m en t s. Ge mt u z u ma b o z og amici n was t h e first ADC u si ng cali chea mi c i n, a po t en t DNA mi no r g r oov e b i nd er (a nd no t a mic ro t ubu l e agen t) , app r oved i n 2000 alt hough wit hd raw n fr o m t h e mar ket i n 2013 due t o f a il ed con firmat o r y st ud ies . Ma y ta n si no i d s a nd a u ristati ns a r e unr el a t ed, a lt hough a r e bo t h t ubu li n - b i nd i ng a g e n ts o f t h e v i n ca b i nding site a nd i nh i b it t ubu li n po l y merizati on . T h e y are 100 - t o 1,000 -f o l d mor e c y t o t ox i c t ha t m os t cance r ch em o t h era p e u tics . Drug m ay t ans i no i d - 1 ( DM1 ) is t h e c h em o t h era p e u tic d eli v ere d u si ng a t h i o et h er li nke r i n t he ADC ado -trast u z u ma b emta n si n e ( T -DM 1 ) t h at w as F DA a pp r oved f o r pa ti en t s wi t h HER 2 - po siti v e metastatic b reast ca n ce r pr e v i ous l y tr ea t ed w it h tr as t u z u ma b a nd ta x a n e c h em o t h era p y I n t he i n te rn ati ona l phase III s t ud y , t h ere was a 3.2 -m on t h im p r ov e d p r og ressi on - fr ee s urv i va l a m ong pa ti en t s t h at recei v e d T -DM 1 c o m p are d t o t ho se r ecei v i ng s t anda r d tr ea tm en t w it h ca p ecita b i n e a nd la p ati n i b . Des p ite a po te n t c he m o t he r apeu ti c, t he t o lera b ilit y was m u c h b etter i n t h e

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e xp e r im en t a l a rm , wh i ch was do se d at 3.6 m g / kg i n tra v e nou sl y e v er y 21 d a y s . The m os t co mm on s i de e f fects i n t h e trial were t h r o m bo c y t op e n ia (12.8%), tr ans i en t tr ansa mi n itis ( 4.3 %) , as well as n a u sea , fati gu e , m y al g ia s, and a rt h r a l g i as M ono met hy l au ri s t a ti n E ( M MAE) is li nk e d t o a m ono cl on al a n ti body a g ai n st CD30 as an ADC ( b re n t ux ima b v e do ti n, SGN 35 ) a nd a pp r ov e d f o r r e fr act ory Hodgk i n l y m pho ma o r a n a p lastic lar g e cell l y m pho ma . T h e li nk e r is a pep ti de - based subs trate f o r cat h e p si n -B a nd t h ere by d esi gn e d to d etect th e l ysoso m e / endoso me c o m p artme n t f o r d r ug release . D o se-limiti ng t ox i c iti es i nc l ude t h r o m bo c y t op e n ia , hyp er g l y cemia , d iarr h ea , and vo miti n g , and t he m os t co mm on si d e e f fects i n t h is h ea v il y p retreate d popu lati on (i nc l ud i ng au t o l ogou s stem cell tra n s p la n t) i n cl ud es p eri ph era l n e urop a thy ( 42 %) , nausea ( 35 %) , a nd fati gu e ( 34 %) . T h e FDA b lac k box w a rn i ng i nc l udes con tr a i nd i c ate d u se wit h b le o m y ci n du e t o i n crease d pu lm ona r y t ox i c it y and t he ris k o f J ohn C unn i ngh am (JC) v ir u s – i ndu ce d progr es s i ve m u ltif oca l l euko e n ce ph al op at h y . Re po rts o f se v ere p a n creati tis a r e als o e m e r g i ng. M I T OT I C MO T OR P RO TEI N INHIBI T ORS Auror a Ki nase and P o l o li ke Ki n ase I nh i b it o rs Auror a ki nases a r e se ri ne /t h r eon i n e k i n ases cr u cial f o r mit o sis i n t h eir r ec ru it men t o f mit o ti c m o t o r pr o tei n s f o r s p i nd le f o rmati on. T h e y are p a r tic u l a rl y ove r exp r essed i n h i gh g r o wt h rate t u m o rs . A u r o ra A a nd B k i n ases ar e exp r essed g l oba ll y t h r oughou t all tiss u es , a nd A u r o ra C k i n a se is e xpr e ssed i n t es t es and pa rtici p ates i n mei o sis . A u r o ra A k i n ase is e xpr ess ed and fr equen tl y a m p lifie d i n ma ny e p it h elial t u m o rs a nd im p licat ed i n t he mi c r o t ubu l e- tar g ete d a g e n t-resista n t ph e no t yp e . A u ror a A k i n ase i n t e r ac t s w it h p53, a nd t h ere is e v i d e n ce t h at p53 wil d -t yp e t u m or s a r e m o r e sens iti ve t o a u r o ra A k i n ase i nh i b it o rs t h a n p53 m u ta n t t u m or s . M L N - 8237 has an I C 50 o f 1 n m f o r a u r o ra A k i n ase a nd >200 n m for au r o r a B k i nase and i s i n cli n ical d e v el op me n t f o r treatme n t-rela ted n e uro e ndoc ri ne p r os t a t e canc e r . , T h e mai n do se-limiti ng t ox icit y o f t h ese a gen t s i s neu tr open i a. P o l o li k e k i n ases (PLKs) are seri n e o r t h re onine

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k i n ases cr uc i a l f o r ce ll cyc l e pr o cess . O v ere xp ressi on o f PLKs h as b ee n s hown t o be r e l a t ed t o h i s t o l og ic g ra d i ng a nd poo r p r ogno sis i n se v eral t yp es of cance r . B I- 2536 and O N 01910 are PLK i nh i b it o rs i n earl y cli n i cal d e v el opmen t K i n esi n S p i nd l e Pr o t e i n I nh i b it o r I s p i n esib K i n esi n sp i nd l e p r o t e i n ( K SP; als o kno w n as EG 5 ) is a k i n esi n m o t o r pro tei n requ ir ed t o es t ab li sh m it o tic-s p i nd le b i po larit y Se v eral KSP i nh i b it ors have been eva l ua t e d i n earl y ph ase cli n ical trials . SB- 715992 ( is p i n es ib ) i s a s m a ll-m o l ecu le i nh i b it o r o f KSP A TPase a nd h as b ee n e v al u ate d i n t wo d i f f e r en t sch e du les T h e do se-limiti ng t ox icit y is n e u t ropen i a. I sp i nes i b was f o u nd t o b e i n acti v e i n ph ase 2 st ud ies e v al u atin g e f fi cacy i n pa ti en t s wit h castrati on -resista n t a nd lar g el y do ceta x el-r es i s t an t p r os t a t e c a n ce r , a dv a n ce d re n al ca n ce r , a nd h ea d a nd n ec k ca nce r . – M E C HAN IS M S O F R ESIS T ANCE T O MICROTUBULE INHIBI T OR S Drug r e s i s t ance i s o ft en co mple x a nd m u ltifacete d a nd ca n i nvo l v e d i v er se mec h a nis m s such as ( 1 ) f ac t or s t h at re du ce t h e a b ilit y o f d r ug s t o reac h t h ei r cell u l a r t a r ge t ( e.g., ac tivati on o f d et ox ificati on p at h wa y s a nd d ec r eas ed d r ug accu m u l a ti on) ; ( 2 ) m od ificati on s i n t h e d r ug ta r g et; a nd (3 ) e v e n ts downs tr ea m o f t he t a r g et (e .g., d ecrease d se n siti v it y t o, o r d efecti ve, a pop t o ti c s i gna l s ) . Many t ubu li n b i nd i ng a g e n ts are s ub strates f o r m u lti d r ug t r a n s por t e r s such as P- g l ycopro tei n a nd t h e m u lti d r ug resista n ce g e n e ( M D R 1 ) . Th e MD R1 - encoded gene p r odu ct MDR 1 (ABC s ub famil y B 1 ; ABCB 1 ) a nd M DR2 ( ABC sub f a mil y A BCB 4 ) are t h e b est-c h aracterize d ABC t r a n s por t e r s t hough t t o con f e r d r ug resista n ce t o ta x a n es . MDR-rela ted ta x a n e r e s i s t ance can be r ever se d by ma ny classes o f d r ug s , i n cl ud i ng t he calci u m channe l b l ocke r s, cyc l o s po ri n A , a nd a n tiarr hy t h mic a g e n ts . ,

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How e v e r , t he c li n i ca l u tilit y o f t h is a pp r o ac h h as n e v er b ee n p r ov e n,

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a n t hr acy c li nes ) BRCA1 is a t u m o r -s upp ress o r g e n e wit h DNA d ama g e r esponse and r epa i r , as well as cell c y cle c h ec kpo i n t acti v ati on, wh ic h ex p l a i ns why it s l oss lea d s t o e nh a n ce d cis p lati n se n siti v it y .

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BRC A1 a l so i nd ir ec tl y r egu lates micr o t ubu le dyn amics a nd sta b ilit y a n d ca n f a vo r ab l y con tr o l how mi c r o t ubu les res pond t o p aclita x el treatme n t via t h ei r ass oc i a ti on w it h p r o - casp ase- 8. T h e l o ss o f BRCA 1 ca n lea d t o im p ai r e d t axane -i nduced ac ti v ati on o f a pop t o sis du e t o micr o t ubu les t h at a r e m ore dyna mi c and l ess sus ce p ti b le t o ta x a n e-i ndu ce d sta b ilizati on a nd prox imi ty -i nduced ac ti va ti on o f cas p ase- 8 si gn ali ng In a dd iti on t o r es i s t ance, ce rt a i n t u m o r s ub t yp es ma y b e se n siti v e t o t h e ta x a n e d os i ng schedu l e. I n t w o ra ndo mize d trials o f l o w- do se , wee k l y p aclita x el , t he l u mi na l b r eas t c a n cer s ub t yp e was f ound t o h a v e a b etter ou tc o m e co m pa r ed w it h t he con tr o l arm . T h is s ugg ests t h at no t on l y t h e drug, but a l so t he schedu l e ma y i n fl u e n ce t h e res pon se t o t h era py a nd t hat g e no mi c app r oaches m ay r ev eal t h ese i n si gh ts R E F E R ENC ES 1. Kava ll a ri s M. M i c r o t ubu les a nd resista n ce t o t ubu li n - b i nd i ng a g e nts. N at Re v Cance r 2010 ; 10 : 194–204. 2. Noga l es E . Str uc t u r a l i n si gh ts i n t o micr o t ubu le f un cti on. A nn Rev Bi ophy s B i o m o l Str uc t 2001 ; 30 : 397–420. 3. W an i MC, T ay l o r H L , W all ME , et al . Pla n t a n tit u m o r a g e n ts . VI . I s o lati on and s tr uc t u r e o f t axo l , a nov el a n tile uk emic a nd a n tit u m o r a g en t fro m T a xus b r ev if o li a. J A m Ch em S o c 1971 ; 93 : 2325–2327. 4. Ro w i nsky E , Donehowe r R . A n timicr o t ubu le a g e n ts . I n : De V ita- Skin V T , H ellm ann S , Rosenbe r g SA , e d s . Ca n cer: Pri n ci p les a nd Practice o f On c o l ogy. 5 t h ed. P h il ade l phi a: Li pp i n c o tt-Ra v e n ; 1997. 5. V ri gnaud P , S é mi ond D , Leje un e P , et al . Precli n ical a n tit u m o r acti v it y o f cabaz it axe l , a se mis yn t h etic ta x a n e acti v e i n ta x a n e-resista n t t u m or s . C li n Cance r Res 2013 ; 19 : 2973–2983.

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6. Sp a r ano JA. T axanes f o r b reast ca n cer: a n e v i d e n ce- b ase d re v iew of r a ndo mi zed phase II and phas e III trials . Cli n Breast Ca n cer 2000 ; 1 : 32– 4 0. 7. Ma m ounas E , L e i nbe r sky B , Br y a n t J , et al . Paclita x el after doxorubic i n p l us cyc l ophosph ami d e as a d j uv a n t c h em o t h era py f o r nod e- po siti v e b r eas t cance r: r esu lt s fr o m NSABP B- 28. J Cli n O n c o l 2005 ; 23 : 3686–3696. 8. Bo no mi P , K im KM, Faircl ough D , et al . C o m p aris on o f s u r v i v al a nd qu alit y o f lif e i n advanced non -small-cell l ung ca n cer p atie n ts treate d w ith t wo do se l eve l s o f pac lit axe l c o m b i n e d wit h cis p lati n v ers u s et opo si d e with cis p latin: r esu lt s o f an E as t e r n C oop erati v e O n c o l ogy Gr oup trial . J Cli n On c o l 2000 ; 18 : 623–631. 9. Ma rti n M, Pi enkowsk i T , Mac k e y J , et al . A d j uv a n t do ceta x el f o r nod e -pos iti ve b r eas t cance r . N E ng l J Me d 2005 ; 352 : 2302–2313. 10. Jo nes SE , Er ban J, Ove rm oy er B , et al . Ra ndo mize d ph ase III st udy of do cet axe l co m pa r ed w it h paclita x el i n metastatic b reast ca n ce r . J Cli n On c o l 2005 ; 23 : 5542–5551. 1 1. T annock I F , de W it R, Berr y WR , et al . D o ceta x el p l u s p re dn is on e o r mit ox a n tr one p l us p r edn i son e f o r a dv a n ce d p r o state ca n ce r . N E ng l J M ed 2004 ; 351 : 1502–1512. 12. V an Cu t se m E , Mo i sey e nko V , Tj u la nd i n S , et al . P h ase III st udy of do ceta x el and c i sp l a ti n p l us fl uo r ou racil c o m p are d wit h cis p lati n a nd f l uorourac il as fir s t-li ne t he r apy f o r a dv a n ce d g astric ca n cer: a re po rt o f the V325 St udy G r oup. J C li n On c o l 2006 ; 24 : 4991–4997. 13. Sc h i f f P B, F an t J, Ho rwitz SB . Pr o m o ti on o f micr o t ubu le assem b l y i n v it ro b y t axo l . Na t u r e 1979 ; 277 : 665–667. 14. Noga l es E . Str uc t u r a l i n si gh t i n t o micr o t ubu le f un cti on. A nnu Rev Bi ophy s B i o m o l Str uc t 2001 ; 30 : 397–420. 15. Da r shan M S , L o ft us M S , T h a d a n i-M u ler o M , et al . T a x a n e-i ndu c ed b l o c k a d e t o nuc l ea r accu m u l a ti on o f t h e a nd r og e n rece p t o r p re d icts cli n i cal

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25. Ch auhan V P , St y li anopou l o s T , Marti n JD , et al . N o rmalizati on o f t u m our b l ood vesse l s im p r ove s t h e d eli v er y o f n a no me d ici n es i n a size- d e p e nd e n t m anne r . Na t Nanot ec hno l 2012 ; 7 : 383–388. 26. G r ad i sha r W , Tj u l and i n S , Da v i d s on N , et al . P h ase III trial o f n a nop a r ti c l e a l bu mi n - bound p aclita x el c o m p are d wit h po l y et hy late d cast o r o il -b ased pac lit axe l i n wo m e n wit h b reast ca n ce r . J Cli n O n c o l 2005 ; 23 : 7794–7803. 27. So c i nsk i MA, Bonda r enko I , Karase v a NA , et al . W ee k l y n a b - p aclita x el i n co m b i na ti on w it h car bop lati n v ers u s s o l v e n t- b ase d p aclita xel p l u s ca rbop l a ti n as fir s t-li ne t h era py i n p atie n ts wit h a dv a n ce d non– sma ll -cell l ung cance r: fi na l r esu lt s o f a P h ase III trial . J Cli n O n c o l 2012 ; 30 : 2055–2062. 28. V on Ho f f DD, Er v i n T , Are n a F P , et al . I n crease d s u r v i v al i n p a n c r eati c cance r w it h nab - pa clita x el p l u s g emcita b i n e . N E ng l J Me d 2013 ; 369 : 1691–1703. 29. Sp a rr eboo m A, S c ri p t u re CD , T rie u V , et al . C o m p arati v e p recli n ic al a nd cli n i ca l pha rm acok i ne ti cs o f a crem opho r-free , n a nop article al bu mi n - bound pac lit axe l ( AB I- 007 ) and p aclita x el f o rm u late d i n crem opho r ( T a xo l ). C li n Cance r Res 2005 ; 1 1 : 4136–4143. 30. Y a r d l ey DA. nab -P ac lita x el mec h a n isms o f acti on a nd d eli v er y . J C on t ro l Re l ease 2013 ; 170 : 365–372. 31. Desa i N, T ri eu V , Y ao Z, et al . I n crease d a n tit u m o r acti v it y , i n t r at umo r pac lit axe l concen trati on s , a nd e ndo t h elial cell tra n s po rt o f c r em opho r -fr ee, a l bu mi n - bound p aclita x el , ABI- 007, c o m p are d wit h c r em opho r - based pac lit axe l . Cli n Ca n cer Res 2006 ; 12 : 1317–1324. 32. Ny m an D W , Ca m pbe ll KJ , Hers h E , et al . P h ase I a nd ph a r ma cok i ne ti cs tri a l o f AB I- 007, a nov el n a nop article f o rm u lati on o f p aclita x el i n pa ti en t s w it h adv a n ce d nonh emat o l og ic mali gn a n cies . J Cli n On c o l 2005 ; 23 : 7785–7793.

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hour i nfus i on eve r y 3 weeks i n p atie n ts wit h a dv a n ce d s o li d t u m o rs . Cli n Ca n ce r Res 2009 ; 15 : 723–730. 43. D i é r as V , L o rt ho l a r y A, La u re n ce V , et al . Ca b azita x el i n p atie n ts w it h a dvanced so li d t u m ou r s : res u lts o f a P h ase I a nd ph armac ok i n etic st ud y . Eu r J Cance r 2013 ; 49 : 25–34. 44. M it a AC, Den i s L J, Ro wi n s ky EK , et al . P h ase I a nd ph a r ma cok i ne ti c s t udy o f XR P 6258 (RPR 1 16258 A) , a nov el ta x a n e , a d mi n is te r ed as a 1 - hou r i n f us i on e v er y 3 wee k s i n p atie n ts wit h a dv a n c ed s o li d t u m o r s. C li n Cance r Res 2009 ; 15 : 723–730. 45. Y a r ed JA, T kaczuk KH. U pd ate on ta x a n e d e v el op me n t: n ew a n al ogs a nd n ew f o rm u l a ti ons. D r ug Des De v el T h er 2012 ; 6 : 371–384. 46. Ba as P , S zczesna A, A l b ert I , et al . P h ase I/II st udy o f a 3 wee k l y o r al ta x a n e ( D J - 927 ) i n pa ti en t s wi t h rec u rre n t , a dv a n ce d non -small cell l ung ca n ce r . J T ho r ac Onco l 2008 ; 3 : 745–750. 47. V i gano L , L oca t e lli A, Grasselli G , et al . Dr ug i n teracti on s o f p aclita x el and doce t axe l and t h eir rele v a n ce f o r t h e d esi gn o f c o m b i n ati on t h e r a p y . I nves t New D r ugs 2001 ; 19 : 179–196. 48. Kud l ow it z D, Mugg i a F . Defi n i ng ris k s o f ta x a n e n e u r op at hy : i n si gh ts fr o m r ando mi zed c li n ical trials . Cli n Ca n cer Res 2013 ; 19 : 4570 – 4577. 49. Henn i ngsson A, Ka rl ss o n MO , V i g a nò L , et al . Mec h a n ism- b ase d ph a r ma cok i ne ti c m ode l f o r pa clita x el . J Cli n O n c o l 2001 ; 19 : 4065–4073. 50. Sis sung T , M r oss K, St e i nb e r g S , et al . Ass o ciati on o f ABCB 1 g e no t ypes w it h pac lit axe l-m ed iate d p eri ph eral n e u r op at hy a nd n e u tr op e nia. Eur J C ance r 2006 ; 42 : 2893–2896. 51. Ma r sh S , P au l J, K i ng C, et al . P h armac og e n etic assessme n t o f t ox icit y and ou t co m e a ft e r p l a ti nu m p l u s ta x a n e c h em o t h era py i n ov aria n ca n ce r : t he S co tti sh Rando mise d T rial i n O v aria n Ca n ce r . J Cli n O n c o l 2007 ; 25 : 4528–4535.

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52. Bal dw i n RM, Owza r K, Zem bu ts u H , et al . A g e no me-wi d e ass o ciat ion s t udy i den tifi es nov el l o ci f o r p aclita x el-i ndu ce d se n s o r y p e r i ph e ra l neu r opa t hy i n CA LGB 40101. Cli n Ca n cer Res 2012 ; 18 : 509 9 – 5109. 53. Ru go H, Ba rr y W , Mo r eno As p itia A , et al . CALGB 40502 /NCC TG N063H : Rando mi zed phase I I I trial o f wee k l y p aclita x el (P) c o m p are d t o w ee k l y nanopa rti c l e a l bu mi n bound n a b - p aclita x el (NP) o r i x a b e p il on e ( I x ) w it h or wit hou t bevac i zu m ab (B) as first-li n e t h era py f o r l o call y rec u rre nt or meta s t a ti c b r eas t cance r (MBC) . J Cli n O n c o l 2012 ; 30. 54. Ba ke r J, A j an i J, S co tt é F , et al . D o ceta x el-relate d si d e effects a nd t h ei r ma nage m en t . E u r J Onco l N u rs 2009 ; 13 : 49–59. 55. Lee J, S wa i n S . P e ri phe ral n e u r op at hy i ndu ce d by micr o t ubu le-sta b ilizin g agen t s. J C li n Onc ol 2006 ; 24 : 1633–1642. 56. A l sa m a r a i S , Cha r p i dou AG , Matt h a y RA , et al . P n e u m on itis rela ted t o do cet axe l: case r epo rt and re v iew o f t h e literat u re . I n V i vo 2009 ; 23 : 6 3 5– 637. 57. Du mitr a S , Si de ri s L , Leclerc Y , et al . Ne u tr op e n ic e n ter o c o litis a nd do ceta x el neoad j uvan t che m o t h era p y . A nn O n c o l 2009 ; 20 : 795–796. 58. de Bono J S , Ouda r d S , Oz gu r og l u M , et al . Pre dn is on e p l u s ca b azita xe l o r mit oxan tr one f o r metastatic castrati on -resista n t p r o state ca n ce r p r og r ess i ng a ft e r doce ta x el treatme n t: a ra ndo mise d op e n -la b el tr ial. L a n cet 2010 ; 376 : 1 147– 1 154. 59. Zhou XJ, Pl ac i d i M, R a h ma n i R . U p ta k e a nd meta bo lism o f v i n ca al k al o i ds by fr esh l y i so l a t ed hu ma n h e p at o c y tes i n s u s p e n si on. A n tica nce r Res 1994 ; 14 : 1017–1022. 60. Zhou J, G i annakakou P . T a r g eti ng micr o t ubu les f o r ca n cer c h em o t he r ap y . Cu rr Med Ch em A n tica n cer A g e n ts 2005 ; 5 : 65–71. 61. Jor dan MA, W il son L . Micr o t ubu les as a ta r g et f o r a n tica n cer d r ugs. N at Re v Cance r 2004 ; 4 : 253–265.

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73. T annock I F , de W it R, Berr y WR , et al . D o ceta x el p l u s p re dn is one o r mit ox a n tr one p l us p r edn i son e f o r a dv a n ce d p r o state ca n ce r . N E ng l J M ed 2004 ; 351 : 1502–1512. 74. Lee JJ, Ke ll y WK. E po t h il on es: t ubu li n po l y merizati on as a nov el ta r g et fo r p r os t a t e cance r t he ra p y . Nat Cli n Pract O n c o l 2009 ; 6 : 85–92. 75. Ke ll y WK. E po t h il one s i n p r o state ca n ce r . Ur o l O n c o l 20 1 1 ; 29 : 3 5 8– 365. 76. Ke ll y K, Z o lli nge r M, L o zac’ h F , et al . Meta bo lism o f p at up il on e in p atie n ts w it h advanced so li d t u m o r mali gn a n cies . I nv est New Dr ug s 2013 ; 31 : 605–615. 77. T r a il P A, W ill ne r D, L a sc h SJ , et al . C u re o f x e nog rafte d hu ma n ca r ci nomas by BR96 - doxo r ub ici n imm uno c on j ug ates . Scie n ce 1993 ; 261 : 212–215. 78. Cart e r P J, S en t e r P D. A n ti body - d r ug c on j ug ates f o r ca n cer t h era p y . Ca n ce r J 2008 ; 14 : 154–169. 79. Do r on i na S O, T ok i B E , T o r gov M Y , et al . De v el op me n t o f po te n t m ono cl ona l an ti body au ri s t a ti n c on j ug ates f o r ca n cer t h era p y . Nat Bi o tec h n o l 2003 ; 21 : 778–784. 80. Lew i s P h illi ps GD, Li G , D ugg er DL , et al . T a r g eti ng HER 2 - po sit ive br east c ance r w it h tr as t uzu ma b -DM 1, a n a n ti body– c y t o t ox ic d r ug c on j ug a te. Cance r Res 2008 ; 68 : 9280–9290. 81. V e rm a S , M il es D, G i ann i L , et al . T rast u z u ma b emta n si n e f o r HE R 2-pos iti ve advanced b r e ast ca n ce r . N E ng l J Me d 2012 ; 367 : 1783– 1791. 82. Oke l ey NM, M i ya m o t o JB , Z h a ng X , et al . I n tracell u lar acti v ati on o f S GN-35 , a po t en t an ti- CD30 a n ti body - d r ug c on j ug ate . Cli n Ca n cer Res 2010 ; 16 : 888–897.

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83. Y ounes A, Ba rtl e tt N L , Le on ar d J P , et al . Bre n t ux ima b v e do ti n (SGN-35 ) f o r r e l apsed CD30 - po siti v e l y m pho mas . N E ng l J Me d 2010 ; 363 : 1812–1821. 84. Y ounes A. B r en t ux im ab v e do ti n f o r t h e treatme n t o f p atie n ts wit h Hodgk i n l y m pho m a. He m a t o l O n c o l Cli n N o rt h Am 2014 ; 28 : 27–32. 85. Gandh i M, E vens AM, Fe n s k e TS , et al . Pa n creatitis i n p atie n ts t r eate d w it h b r en t ux im ab vedo ti n : a p re v i ou sl y un rec ogn ize d seri ou s a dv e r se even t . B l ood 2013 ; 122 : 4380. 86. Mosque r a JM, Be ltr an H , Par k K , et al . C on c u rre n t AURKA a nd M Y C N gene a m p lifi ca ti ons a re h ar b i ng ers o f let h al treatme n t-relate d n e uro e ndoc ri ne p r os t a t e canc e r . Ne op lasia 2013 ; 15 : 1–10. 87. U j hazy P , St ewa rt D. D NA Re p ai r . J T ho rac O n c o l 2009 ; 4 :S 1068– S 1070. 88. G r een MR, W oo l e r y J E , Ma h a d e v a n D . U pd ate on a u r o ra k i n ase ta r g ete d t he r apeu ti cs i n onco l og y . E xp ert O p i n Dr ug Disc ov 20 1 1 ; 6 : 291 – 307. 89. Ja ckson JR, P a tri ck D R , Dar MM , et al . T a r g ete d a n ti-mit o tic t h e r a p ies: can we im p r ove on t ubu li n a g e n ts? Nat Re v Ca n cer 2007 ; 7 : 1 0 7– 1 17. 90. T ang P A, Si u LL , Chen EX , et al . P h ase II st udy o f is p i n esi b i n r ec urr e n t o r m e t as t a ti c squa m ou s cell carci no ma o f t h e h ea d a nd n ec k. Inv est New D r ugs 2008 ; 26 : 257–264. 91. Be e r T M, Go l d m an B, S yno l d T W , et al . S ou t h west on c o l ogy g r oup ph ase II s t udy o f i sp i nes i b i n and r og e n -i nd e p e nd e n t p r o state ca n cer pr e v i ous l y tr ea t ed w it h t axan es . Cli n Ge n it ou ri n Ca n cer 2008 ; 6 : 103–109. 92. Lee R T , Beek m an K E , H u ssai n M , et al . A un i v ersit y o f c h ica go c on s or ti u m phase II tri a l o f SB- 715992 i n a dv a n ce d re n al cell ca n ce r . Cli n G e n it ou ri n Cance r 2008 ; 6 : 21–24.

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93. Per ez E A. M i c r o t ubu l e i nh i b it o rs: d i f fere n tiati ng t ubu li n -i nh i b iti n g a g e n ts based on m echan i s m s of acti on, cli n ical acti v it y , a nd resista n ce . Mol Ca n ce r T he r 2009 ; 8 : 2086–2095. 94. Go tt es m an MM, F o j o T , Bates SE . M u lti d r ug resista n ce i n ca n cer : ro le of A TP- dependen t tr anspo rters . Nat Re v Ca n cer 2002 ; 2 : 48–58. 95. Foj o A T , Mene f ee M. Micr o t ubu le ta r g eti ng a g e n ts: b asic mec h a nis m s o f m u lti d r ug r esi sta n ce (MDR) . Semi n O n c o l 2005 ; 32 :S 3–S8. 96. Mozze tti S , F e rli n i C, C on c o li no P , et al . Class III b eta-t ubu li n ov e r e xp r ess i on i s a p r o mi nen t mec h a n ism o f p aclita x el resista n ce i n ov a r ia n cance r pa ti en t s. C li n Ca n cer Res 2005 ; 1 1 : 298–305. 97. D r uk m an S , Kava ll a ri s M . Micr o t ubu le alterati on s a nd resista n ce t o t ubu li n- bi nd i ng agen t s (r ev i ew ) . I n t J O n c o l 2002 ; 21 : 621–628. 98. V e rrill s NM, Kava ll a ri s M . Im p r ov i ng t h e ta r g eti ng o f t ubu li n - b i nd i ng agen t s : l essons fr o m d r ug resista n ce st ud ies . C u rr P h arm Des 2005 ; 1 1 : 1719–1733. 99. O rr GA, V e r d i e r -Pi na r d P , McDai d H , et al . Mec h a n isms o f T a xo l r esista nce r e l a t ed t o mi c r o t ubu les . O n c og e n e 2003 ; 22 : 7280–7295. 100. Monzó M, Rose ll R, S án c h ez JJ , et al . Paclita x el resista n ce i n non -small - cell l ung cance r assoc iate d wit h b eta-t ubu li n g e n e m u tati on s . J Cli n On c o l 1999 ; 17 : 1786–1793. 101. Se ve P , Mackey J, I saa c S , et al . Class III b eta-t ubu li n e xp ressi on i n t u m or c e ll s p r ed i c t s r esponse a nd ou tc o me i n p atie n ts wit h non -small ce ll l ung ca nce r r ece i v i ng pac lit ax el . M o l Ca n cer T h er 2005 ; 4 : 2001–2007. 102. Ba que r o M T , Hanna JA, Ne u meister V , et al . Stat h mi n e xp ressi on a nd its re l a ti onsh i p t o mi c r o tu bu le-ass o ciate d p r o tei n ta u a nd ou tc o me i n br east c ance r . Cance r 2012 ; 1 18 : 4660–4669. 103. Ba que r o M T , L os tritt o K , G u sta v s on MD , et al . E v al u ati on o f progno sti c and p r ed i c ti ve va l u e o f micr o t ubu le ass o ciate d p r o tei n ta u i n

IN T RODUCTION

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In 2001, t he fir s t t y r os i ne - k i n ase i nh i b it o r imati n i b was a pp r ov e d f o r cli n ical u se i n ch r on i c m ye l o i d le uk emia . T h e s p ectac u lar s u ccess o f t h i s f i r st - i n-c l ass agen t ushe r ed i n a tra n sf o rmati on i n ca n cer d r ug d isc ov er y fro m e f f ort s t ha t we r e l a r ge l y b ase d on nov el c y t o t ox ic c h em o t h era py a g e n ts t o an a lm os t exc l us i ve f o c u s on m o lec u larl y tar g ete d a g e n ts acr oss t h e ph a r m aceu ti ca l and b i o t e c hno l ogy i ndu str y a nd aca d emia . T h is c h a pte r s u mma r i zes t h i s r e m a r kab l e p r og ress i n t h is fiel d ov er ~ 15 y ears , wit h t he fo c u s on t he concep t s unde rl y i ng t h is p ara d i g m s h ift as well as t h e c on si d e rab l e cha ll enges t ha t remai n ( ) . Rea d ers i n searc h o f mo r e s p eci f ic de t a il s on i nd i v i dua l d r ug s a nd t h eir i nd icati on s s hou l d c on s u lt t he r ele v a n t d i sease - spec ifi c chapt ers elsew h ere i n t h is vo l u me as well as r e f e r e n c es c it ed w it h i n t h i s ch a p te r . Rea d ers s hou l d als o no te t h at t h e e p i d e r m a l g r ow t h f ac t o r r ece pt o r (EGFR) a nd hu ma n e p i d ermal g r o wt h f act or r ec ep t o r 2 ( H E R2 ) r ecep t o r t y r o si n e k i n ases c ov ere d h ere h a v e al so b ee n s uccess f u ll y t a r ge t ed by m ono cl on al a n ti bod ies t h at e ng a g e t h ese pro tei n s a t t he ce ll su rf ace. T h ese d r ug s , referre d t o as b i o l og ics rat h er t han small m o l ecu l e i nh i b it o r s, a r e c ov ere d i n o t h er c h a p ters . T h e c h a p ter is o r g a n ize d a r ound k i nase t a r g ets rat h er t h a n d iseases a nd, i n te n ti on all y , has a h ist or ic a l fl ow t o m ake ce rt a i n t h ematic po i n ts a nd t o ill u strate t h e b r o a d

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

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EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

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F ro m t he beg i nn i ng, c li n i ca l t r ials o f imati n i b were restricte d t o p atie n ts w it h P h i lade l ph i a ch r o m oso me –po siti v e c h r on ic m y el o i d le uk emia . F o r wh at se e m li ke obv i ous r eason s , t h ere was n e v er a ny seri ou s d isc u ssi on a bou t t r e a ti ng pa ti en t s w it h P h ila d el ph ia c h r o m o s o me –n e g ati v e le uk emi a b eca u se t he assu m p ti on was t h at on l y p atie n ts wit h t h e BCR-ABL f u si on g e n e wo ul d have a chance o f res pond i ng. T h is was clearl y a wise d ecisi on b eca u se he m a t o l og i c r espons e rates a pp r o ac h e d 90 % a nd c y t og e n etic r emissi ons we r e seen i n nea rl y h alf o f t h e p atie n ts i n t h e earl y ph ase st ud ies It was obv i ous t ha t t h e d r ug w o r k e d, a nd imati n i b was a pp r ov e d in r ec ord ti me. Unw itti ng l y , t he po wer o f g e no me- b ase d p atie n t selecti on was d em on st ra t ed i n t he c li n i ca l d e v el op me n t o f t h e v er y first k i n ase i nh i b it o r .

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

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A s w e w ill see, it t ook nea rl y a d eca d e f o r t h is less on t o b e f u ll y lear n e d . T od a y , t he m uch l a r ge r c li n i c al e xp erie n ce , wit h a n arra y o f d i f fere n t k i nase i nh i b it ors ac r oss m any t u m o r t yp es , h as le d t o a m u c h b etter und ersta nd i ng of t h e princ i p l es t ha t d i c t a t e on c og e n e a dd icti on t h at , i n retr o s p ect , were sta r i ng us i n t he f ace. F o r e m os t am ong t h em is t h e no ti on t h at t u m o rs wi th a s o matic mu t a ti on o r a m p lifi c ati on o f a k i n ase d r ug tar g et are m u c h m o re li k el y t o be dependen t on t ha t ta r g et f o r s u r v i v al . He n ce , a p atie n t w ho s e t u m or has such a m u t a ti on i s m u c h m o re li k el y t o res pond t o treatme n t with t h e a pprop ri a t e i nh i b it o r . T h is h as als o le d t o a n ew p ara d i g m at t h e r e gu lat o r y l eve l o f d r ug app ro v al re qu iri ng c od e v el op me n t o f a c o m pan i on d i agno s t i c ( a m o l ecu l a rl y bas e d d ia gno stic test t h at relia b l y i d e n tifies p atie n ts wit h t he m u t a ti on ) w it h t h e n ew d r ug. Af te r ch r on i c m ye l o i d l eu kemia , t h e n e x t e x am p le t o ill u strate t h is pr i n ci p l e was gas tr o i n t es ti na l str o mal t u m o r (GIST) , w h ic h is ass o ciate d w it h m u t a ti ons i n t he K IT t y r o si n e- k i n ase rece p t o r o r , m o re rarel y , i n t h e p latelet -de ri ved g r ow t h f ac t o r (PDGF) rece p t o r Sere nd i p it ou sl y , imatin ib i nh i b its bo t h K IT and t he P DG F rece p t o r; t h eref o re , t h e cli n ical test o f KI T i nh i b iti o n i n G IST f o ll owed qu ic k l y on t h e h eels o f t h e s u ccess i n CML . I n r et ro s p e c t , t he r ap i d p r og r ess ma d e i n t h ese tw o d iseases was b ase d, i n pa r t, on t h e fac t t ha t t he d ri ve r m o lec u lar lesi on (BCR-ABL o r KIT m u tati on, r es p ecti ve l y ) i s p r esen t i n near l y all p atie n ts w ho are d ia gno se d wit h t h es e t wo d isea ses. T he m o l ecu l a r a n al y sis merel y c on firme d t h e d ia gno sis t hat w as ma de us i ng s t anda r d c li ni cal a nd h ist o l og ic criteria . C on se qu e n tl y , cli n ician s cou l d i den tif y t he pa tie n ts m o st li k el y t o res pond b ase d on cli n ical crit e ri a r a t he r t han r e l y on a n ela bo rate m o lec u lar p r o fili ng i nfr ast ruc t u r e t o p r esc r een pa tie n ts . C on se qu e n tl y , cli n ical trials e v al u ati ng k i n ase i nh i b it o r s i n CM L and GIST accr u e d qu ic k l y , a nd t h e t h era p e u tic b e n e f it beca m e c l ea r a lm os t imme d iatel y . Th e no ti on t ha t m o l ecu l a r alterati on o f a d ri v er k i n ase d etermi n es se n siti v it y t o a cogna t e k i nas e i nh i b it o r was f u rt h er v ali d ate d du ri ng t h e d e v el opmen t o f t he dua l E G F R /HER 2 k i n ase i nh i b it o r la p ati n i b. Cli n ica l t r ials of t h i s k i nase i nh i b it o r w ere c ondu cte d i n w o me n wit h a dv a n ce d HE R 2-pos iti ve b r eas t cance r b ase d on earlier s u ccess i n t h ese same p ati ents

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

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w it h t h e m onoc l ona l an ti bod y trast u z u ma b, w h ic h tar g ets t h e e x tracell u l a r do mai n o f t he H E R2 k i nase. L a p ati n i b was i n itiall y a pp r ov e d i n c o m b i na ti on w it h t he cy t o t oxi c a g e n t ca p ecita b i n e f o r w o me n wit h r esista nce t o tr as t uzu m ab , and t h e n was s ub se qu e n tl y a pp r ov e d f o r fron tli ne use i n m e t as t a ti c b r ea st ca n cer i n c o m b i n ati on wit h c h em o t h er apy or hor m ona l t he r ap y , depend i ng on estr og e n rece p t o r stat u s . A k e y i ngr e d ie n t t ha t enab l ed t he c li n ical d e v el op me n t o f la p ati n i b was t h e r outine u se of HER2 gene a m p lifi ca ti on testi ng i n t h e d ia gno sis o f b reast ca n ce r , p i on ee red du ri ng t he deve l opm e n t o f trast u z u ma b se v eral y ears earlie r . This w i d es pr e ad c li n i ca l p r ac ti ce a ll o we d f o r t h e ra p i d i d e n tificati on o f t ho se p atie n ts mos t li ke l y t o bene fit. If la p ati n i b trials h a d b ee n c ondu cte d i n un select ed pa ti en t s, t he c li n i ca l si gn al i n b reast ca n cer w ou l d li k el y h a ve b ee n mi ssed.

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

The Se r endipity of Unexpected Clinical Responses: EGFR in Lung Cancer

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In c on t r a s t t o t he l og i ca l deve l op me n t o f imati n i b a nd la p ati n i b i n m o lec u l a rl y de fi ned pa ti en t popu lati on s , t h e EGFR k i n ase i nh i b it o rs g e f iti n i b and e rl o ti n i b en t e r ed t h e cli n ic wit hou t t h e b e n efit o f s u c h a fo c u se d cli n i ca l deve l op m en t p la n. Alt hough c on si d era b le p recli n ical d a ta im p licat ed E G F R as a cance r d r ug tar g et , t h ere was little i n si gh t i n t o w hich p atie n ts w e r e m os t li ke l y t o ben efit . T h e first cl u e t h at EGFR i nh i b it o rs wou l d have a r o l e i n l ung canc er came fr o m t h e rec ogn iti on by se v eral ast u te cli n i c i ans o f r e m a r kab l e res pon ses i n a small fracti on o f p atie n ts with l ung a denoca r c i no m a F u rt h er st ud ies re v eale d t h e c u ri ou s cli n ical ci r c u ms tance t ha t t hose pa ti e nts m o st li k el y t o b e n efit te nd e d t o b e t ho se who n e ve r s m oked, wo m en, a nd t ho se o f Asia n et hn icit y . Clearl y , t h ere w as a st rong c li n i ca l s i gna l i n a s ubg r oup o f p atie n ts , w ho c ou l d p er h a p s be e nr ic h ed based on t hese c li n ical feat u res , bu t it seeme d t h at a un if y i ng m o lec u l a r l es i on m us t be p r esen t . T h ree aca d emic g r oup s sim u lta n e ou sl y c onv e r ged on t he answe r . Mu tati on s i n t h e EGFR g e n e were d etecte d i n the 10% t o 15 % o f pa ti en t s w it h lung a d e no carci no ma w ho h a d ra d i og ra ph i c

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

The Se r endipity of Unexpected Clinical Responses: EGFR in Lung Cancer

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r es pon s es – It m ay see m surp risi ng t h at m u tati on s i n a g e n e as h i gh l y v isi b le as E G F R and i n such a p re v ale n t ca n cer h a d no t b ee n d etecte d ea r lie r . Bu t t he m o ti va ti on t o s earc h a gg ressi v el y f o r EGFR m u tati on s w as no t t h e r e un til t he c li n i ca l r espon ses were see n. Per h a p s e v e n m o re s urpr isi ng was t he f a il u r e o f t h e ph armace u tical c o m p a ny s pon s o rs o f t he t wo m os t advanced co m pound s , g efiti n i b a nd erl o ti n i b, t o em b race t h is im por ta n t d i scove r y and r e f o c u s f u t u re cli n ical d e v el op me n t p la n s on p atie n ts wit h E G F R m u t an t l ung a d e no carci no ma . B u t t ha t was 2004, when t h e p re v aili ng a pp r o ac h t o ca n cer d r ug d e v el opmen t was an e m p iri c on e o ri g i n all y d e v el op e d (wit h g reat s u cce ss ) for c y t otox i c agen t s. T yp i ca ll y , small nu m b ers o f p atie n ts wit h d i f fere n t ca n ce r s we r e tr ea t ed i n a ll co mer ph ase I st ud ies ( no e n ric h me n t f o r s ubgroups ) w it h t he goa l o f e liciti ng a cli n ical si gn al i n at least on e t u mor t yp e . A s i ng l e - agen t r esponse rate o f 20 % t o 30 % i n a d isease-s p ecific ph ase II tri a l wou l d j us tif y a ra ndo mize d ph ase III re g istrati on trial , w h er e t h e t yp i ca l endpo i n t f o r d r ug a pp r ov al is time t o p r og ressi on o r s u r v i v al . C y t o t ox i cs we r e a l so t yp i ca lly e v al u ate d i n c o m b i n ati on wit h e x isti ng sta nd a rd o f ca r e tr ea tm en t (t yp icall y a pp r ov e d c h em o t h era py a g e n ts) wi th t h e go al o f i nc r eas i ng t he r espon se rate o r e nh a n ci ng t h e du rati on o f r es pon s e. ( No t e : T he use o f the p ast te n se h ere is i n te n ti on al . As we will see late r i n t h i s chap t e r , nea rl y a ll ca n cer d r ug d e v el op me n t t od a y is b ase d o n selecti ng pa ti en t s w it h a ce rt a i n m o lec u lar p r o file . ) Th e c li n i ca l deve l op m en t o f g efiti n i b a nd erl o ti n i b f o ll o we d t h e c y t o t ox i c m ode l . Bo t h d r ugs h a d similarl y l o w bu t c onv i n ci ng si ng le-a gent r es pon s e r a t es ( 10 % t o 15 %) in c h em o t h era py -refract o r y , a dv a n ce d l ung ca n ce r . I n deed, ge fiti n i b was o ri g i n all y g ra n te d accelerate d a pp r ov al by t he U. S . F ood and D r ug Ad mi n i s trati on (FDA) i n 2003 b ase d on t h e im p res sive n at ur e o f t hese r esponses, con ti ng e n t on t h e c o m p leti on o f f o rmal ph ase III st ud ies w it h su r v i va l endpo i nt s . T h e s pon s o rs o f bo t h d r ug s , t h eref o re , c ondu cte d phase III r eg i s tr a ti on st ud ies i n p atie n ts wit h c h em o t h era py - r e fr act or y , advanced s t age l ung ca n cer bu t wit hou t p rescree n i ng p atie n ts f o r EG FR m u t a ti on s t a t us. (I n f a i rn ess , t h ese trials were i n itiate d p ri o r t o t he d isc ov e ry o f E G F R m u t a ti ons i n l ung ca n cer bu t st udy ame nd me n ts c ould

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

The Se r endipity of Unexpected Clinical Responses: EGFR in Lung Cancer

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h a v e b e en cons i de r ed. ) Erl o ti n i b was a pp r ov e d i n 2004 on t h e b asis o f a m od est s u r v i va l advan t age ov er p lace bo (t h e BR .21 trial); ho we v e r , g e f iti n i b f a il ed t o de m ons tr a t e a s u r v i v al a dv a n ta g e i n esse n tiall y t h e sa me p atie n t popu l a ti on . T h i s d i f fere n ce i n ou tc o me was s u r p risi ng b eca u s e t h e t wo d r ugs have h i gh l y s imilar c h emical str u ct u res a nd b i o l og ic prop e r tie s. P e r haps t he m os t im po rta n t d i f fere n ce was d r ug do se . Erl o ti nib w as g i ven a t t he m ax im u m t o lerate d do se , w h ic h p r odu ces a h i gh fre qu e ncy of r as h and d i a rr hea. Bo t h s i de e f fects are p res u me d on t a r g et c on se qu e nces of EG F R i nh i b iti on because EGFR is h i gh l y e xp resse d i n s k i n a nd g ast ro i n t es ti na l ep it he li a l ce lls . I n c on trast , g efiti n i b was do se d sli gh tl y l ow e r t o miti ga t e t hese t ox i c ities , wit h t h e rati on ale t h at res pon ses were clea r l y d ocu m en t ed a t l owe r d o ses . In p ar a ll e l w it h t he s i ng l e - ag e n t ph ase III trials i n c h em o t h era py - r e fr act ory pa ti en t s, bo t h ge fiti n i b a nd erl o ti n i b were st ud ie d as a n up fr o n t t h e r a py f o r advanced l ung can cer t o d etermi n e if eit h er w ou l d im p r ov e t he e f f icac y o f s t anda r d doub l e t (car bop lati n / p aclita x el o r g emcitabi ne / c i sp l a ti n ) che m oth era py w h e n all t h ree d r ug s were g i v e n i n c o m b i na ti on. T hese tri a l s, t e rme d IN T AC T - 1 a nd IN T AC T - 2 ( g efiti n i b w ith eit h e r ge m c it ab i ne / c i sp l a ti n o r wit h car bop lati n / p aclita x el) a nd TRIBUTE ( e r l o ti n i b w it h ca r bop l a ti n / pac lita x el) , c o llecti v el y e n r o lle d ov er 3,000 p atie n ts . E xc it e m en t i n t he on c o l ogy c o mm un it y was h i gh b ase d on the clea r si ng l e - agen t ac ti v it y o f b o t h EGFR i nh i b it o rs . B u t , bo t h trials were s p ectac u l a r f a il u r es ; ne it he r d r ug s ho we d a ny b e n efit ov er c h em o t h era p y al on e . The f ac t t ha t E G F R m u tati on s are p rese n t i n on l y 10 % t o 15 % o f p atie n ts ( i .e., t hose li ke l y t o b e n efit) p r ov i d e d a l og ical e xp la n ati on. T h e cli n ical si gna l fr o m t hose who se t u m o rs h a d EGFR m u tati on s was li k el y d il u te d ou t by a ll t he pa ti en t s who se t u m o rs h a d no EGFR alterati on s , m any of who m bene fit ed fr o m che m o t h era p y . Th e conve r gence o f t he EGFR m u tati on d isc ov er y wit h t h ese cli n ical t r ial r es u lt s w ill be r e m e m be re d as a remar k a b le time i n t h e h ist o r y o f ta r g ete d cance r t he r ap i es, no t j u st f o r t h e im po rta n t r o le o f t h ese a g e n ts as l ung ca nce r t he r ap i es, bu t a l s o f o r misste p s i n d eci d i ng t h at t h e EGFR g e no t ype shou l d d ri ve tr ea tme n t selecti on. Per h a p s t h e m o st e g re g i ou s err o r

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

The Se r endipity of Unexpected Clinical Responses: EGFR in Lung Cancer

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came fro m a r e tr ospec ti ve an al y sis o f t u m o rs fr o m p atie n ts treate d on t he BR .21 t r i a l , wh i ch conc l uded t h at EGFR m u tati on s d i d no t p re d ict f o r a s urv i v al advan t age (E G F R g e n e am p lificati on w a s ass o ciate d wit h s urv i v al , bu t on l y i n a un i va ri a te a n al y sis . ) T h is c on cl u si on was c on cer ning b eca u se l ess t han 30 % o f pa tie n ts on t h e trial h a d tiss u e a v aila b le f o r EG F R m u tati on ana l ys i s, r a i s i ng que sti on s a bou t t h e a d e qu ac y o f t h e sam p le si ze. F ur t h e rmo r e, t he E G F R m u t a ti on assa y u se d by t h e a u t ho rs was s ub se quen tl y c riti c i zed becau se a si gn ifica n t nu m b er o f t h e EGFR m u tati ons r epo rt ed i n t hese p atie n ts were i n resi du es no t p re v i ou sl y f ound by o t h e rs, who had sequenced t hou sa nd s o f t u m o rs . Ma ny o f t h ese m u tati ons we r e suspec t ed t o b e a n artifact o f w o r k i ng fr o m f o rmali n -fi xed b i op sies . F o rt una t e l y , r ecen t a dv a n ces i n DNA m u tati on d etecti on, u si ng massi v el y pa r a ll e l nex t- gene rati on se qu e n ci ng tec hno l og y , h a v e la r g el y elimi n at ed t h i s conce r n. T hes e n ew p latf o rms are no w b ei ng u se d i n t h e cli n ical s e tti ng. Cli n i ca l i nves ti ga t o r s i n A sia , w h ere a g reater fracti on o f l ung ca n cer s (rough l y 30 %) a r e pos iti ve f or EGFR m u tati on s , a dd resse d t h e qu esti on o f wh et h e r m u t a ti ons p r ed i c t f o r cli n ical b e n efit i n a p r o s p ecti v e trial . I n t h i s st udy k n own as I P A SS , ge fiti n i b was clearl y s up eri o r t o sta nd ar d doub le t c h em o t he r apy as fr on tli ne t he ra py f o r p atie n ts wit h a dv a n ce d EGFR m u tati on–pos iti ve l ung adeno carci no ma . C onv ersel y , EGFR m u tati on– n e g ati v e pa ti en t s f a r ed m uch w o rse wit h g efiti n i b a nd b e n efite d fr o m c h em o t he r ap y . I n add iti on, E G FR m u tati on–po siti v e p atie n ts h a d a m o r e f a vor a b l e ove r a ll p r ognos i s re g ar d less o f treatme n t , i nd icati ng t h at EGF R m u tati on i s a l so a p r ognos ti c b i o mar k e r . T h e I P ASS trial ser v es as a c o m p elli ng exa m p l e o f a p r op erl y d esi gn e d (a nd e x ec u te d ) b i o mar k er- dr i v e n cli n i ca l tri a l . A lt hough t h e rati on ale f o r t h is cli n ical d e v el op me n t st r ate gy had been de m ons tr a t ed y ears earlier wit h BCR-ABL i n le uk emi a, KIT i n G IS T , and H E R2 i n b r e ast ca n ce r , it was d i f fic u lt t o d erail t h e em p i r ic app r oach t ha t had be e n u se d f o r d eca d es i n d e v el op i ng c y t o t ox i c a g e n ts .

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

A Mix of Science and Se r endipity: PDGF Receptor–Driven Leukemias and Sa r coma

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A Mix of Science and Se r endipity: PDGF Receptor–Driven Leukemias and Sa r coma

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

A Mix of Science and Se r endipity: PDGF Receptor–Driven Leukemias and Sa r coma

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Th e d is cove r y o f E G F R m u t a ti on s i n l ung ca n cer (m o ti v ate d by d ramati c cli n ical responses i n a subse t o f p atie n ts treate d wit h EGFR k i n ase i nh i b it ors ) i s t he m os t v i s i b l e e x am p le o f t h e po wer o f b e d si d e-t o - b e n c h scie n ce , bu t it i s no t t he on l y (o r t h e first) s u c h e x am p le fr o m t h e k i n ase i nh i b it or e r a. S ho rtl y a ft e r t he a pp r ov al o f imati n i b f o r CML i n 2001, tw o case r e po rt s docu m en t ed d r a matic remissi on s i n p atie n ts wit h hyp e r e os i noph ili c synd r o m e (HES) , a b l ood d is o r d er c h aracterize d by pro l onged e l eva ti on o f eos i noph il c oun ts a nd s ub se qu e n t o r g a n dy sf un ct ion fro m e o si noph il i n filtr a ti on, w h e n treate d wit h imati n i b . Alt hough H ES r esem b le s m ye l op r o lif e r a ti ve diseases s u c h as CML , t h e m o lec u lar p at hog e nes i s o f H ES was co m p letel y unkno w n at t h e time . Reas on i ng th at t h ese cli n i ca l r esponses m us t b e e xp lai n e d by i nh i b iti on o f a d ri v er k i n a se, a team of l abo r a t o r y - based phy sicia n /scie n tists qu ic k l y searc h e d f o r m u tati ons i n t he t h r ee k i nases kno w n t o b e i nh i b ite d by imati n i b (ABL , KI T , a nd P DG F r ecep t o r) . A BL a nd KIT were qu ic k l y e x cl ud e d, bu t t h e P DG F r e cep t o r α (P DG F R - α ) g e n e was ta r g ete d by a n i n terstitial d eleti on t h at fu s ed t he ups tr ea m FIP 1 L 1 g e n e t o PDGFR- α FIP 1 L 1 -PDGFR- α is a c on stit ut i ve l y ac ti ve t y r os i ne k i n ase , a n al ogou s t o BCR-ABL , a nd is als o i nh i b ite d by im a ti n i b. As w it h EGFR-m u ta n t l ung ca n ce r , t h e m o lec u lar p at hophys i o l ogy o f H ES was d isc ov ere d by d issecti ng t h e mec h a n ism o f r es pon s e t o t he d r ug used t o t r eat it . Th e H ES/FIP 1 L 1 -P DG F R-α st o r y ser v es as a n ice book e nd t o a n ear lie r d isc ov e ry t ha t t he t( 5,12 ) ch r o m o s o me tra n sl o cati on, f ound rarel y i n p atie n ts wit h ch r on i c m ye l o mo no c y tic le uk emia , creates t h e TEL-PDGF R -β fu si on t y r os i ne k i nase Simi l ar t o HES , treatme n t o f p atie n ts wit h t( 5,1 2) t r a n sl o cati on - pos iti ve l euke m i as wit h imati n i b h as als o p r ov e n s u ccessf ul .

EAR L Y SUCCESS E S: T ARGET I NG CANCERS WITH W ELL - K NOWN K INASE M U T A TIONS (BCR-ABL, KI T , HER2)

A Mix of Science and Se r endipity: PDGF Receptor–Driven Leukemias and Sa r coma

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