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20,100 | G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS | null | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,101 | G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS | Pharmacology | null | nan nan | An al og s o f t he decapep ti de Gn R H , h a v e b ee n s yn t h esize d by m od i f ic a ti ons o f pos iti on 6 i n w h ic h t h e l- g l y ci n e h as b ee n e x c h a ng e d f o r a d- ami no ac i d and t he C -t e rmi n al ami no aci d h as b ee n eit h er re p lace d by an et hy lami de o r subs tit u t ed f o r a m od ifie d ami no aci d. T h ese c h a ng es | 6 | 0.05 | 0.01 | 0.02 | 0.01 | 0.01 | 0.01 | 0.05 | 1 |
20,102 | G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS | Pharmacology | null | nan nan | Go ser e li n i s app r ox im a t e l y 100 times m o re po te n t t h a n t h e n at u rall y o cc urr i ng GnRH. Li ke l eup r o li d e , it ca u ses t h e stim u lati on o f LH a nd F SH ac u tel y , and w it h subsequen t a d mi n istrati on, G n RH rece p t o r nu m b ers d ec r eas e, and t he p it u it a r y be c o mes d ese n sitize d wit h d ecreasi ng LH a nd FS H le ve l s. Cas tr a t e l eve l s o f test o ster on e are ac h ie v e d wit h i n 1 m on t h. I n wo me n, gose r e li n i nh i b it s ova ria n a nd r og e n p r odu cti on, bu t ser u m le v el s o f d e hydroep i and r os t e r one su lf at e a nd, t o a lesser e x te n t , a nd r o ste n e d i on e , a r e pr ese rv e d. I n v itr o, gose r e li n h as d em on strate d a n tit u m o r acti v it y i n est rog e n - dependen t MC F 7 hu ma n b reast ca n cer cells a nd LNCaP 2 p r o sta te ca n ce r c e ll s. T he d r ug i s r e l ea se d at a c on ti nuou s mea n rate o f 120 μg pe r d a y i n t he depo t f o rm , w it h p ea k c on ce n trati on s i n t h e ra ng e o f 2 t o 3 μg/L ac h ie v e d. T he m ean vo l u m e o f d istri bu ti on i n si x p atie n ts h as b ee n re po r ted t o b e 13.7 L wh i ch i s cons i s te n t wit h e x tracell u lar fl u i d vo l u me . Go se r eli n i s p ri nc i pa ll y exc r e te d i n t h e u ri n e , wit h a mea n t o tal body clea r a n c e o f 8 L pe r hou r i n pa tie n ts wit h no rmal re n al f un cti on. T h e t o ta l body cl ea r ance i s r educed by a pp r ox imatel y 75 % , wit h re n al dy sf un cti on a nd t h e elimi na ti on ha lf-lif e i n crease d tw o - o r t h reef o l d. H o we v e r , do se a d j u stme n t f o r r ena l i nsu f fi c i en c y do es no t a pp ear t o b e n ecessar y . T h e 5 to 10 h e x a pep ti de and t he 4 t o 10 h e x a p e p ti d e were d etecte d i n u ri n e i n a n im al st ud ies T he t e rmi na l ha lf-l i fe o f go sereli n is a pp r ox imatel y 5 hou rs aft e r s ub c u ta neous i n j ec ti on. Pr o t ein b i nd i ng is l o w , a nd no kno w n d r ug i n te r acti ons have been docu m en te d. | 6 | 0.09 | 0.06 | 0.08 | 0.07 | 0.09 | 0.08 | 0.09 | 1 |
20,103 | G O NADOTRO P IN-RELEASING HOR MO NE AN T AGO N ISTS | null | null | nan nan | G O NADOTRO P IN-RELEASING HOR MO NE AN T AGO N ISTS | 6 | 0.09 | 0.085 | 0.07 | 0.065 | 0.01 | 0.02 | 0.09 | 1 |
20,104 | G O NADOTRO P IN-RELEASING HOR MO NE AN T AGO N ISTS | null | null | nan nan | M od i f icati on t o t he s tr uc t u r e o f G n RH h as res u lte d i n t h e d e v el op me n t o f Gn R H a n t agon i s t co m pounds t h at are c u rre n tl y b ei ng u se d i n t h e treatme nt of pro st a t e cance r . Aba r e li x was i n itiall y a pp r ov e d by t h e FDA i n 2003 as t h e f i r st depo t-i n j ec t ab l e GnR H a n ta gon ist , bu t was s ub se qu e n tl y w it hdr a wn i n 2005. Dega r e li x is a s yn t h eticall y m od ifie d c o m pound with Gn R H a n t agon i s t ac ti v it y t hat was a pp r ov e d f o r u se by t h e FDA i n 2008 f o r | 6 | 0.09 | 0.1 | 0.075 | 0.06 | 0.08 | 0.09 | 0.1 | 2 |
20,105 | G O NADOTRO P IN-RELEASING HOR MO NE AN T AGO N ISTS | null | null | nan nan | t h e ma nage m en t o f p r os t a t e c a n ce r Its e f fect i n p r o state ca n cer treatm ent is t o b l ock t he GnRH r ecep t o r , a nd t h ere by p re v e n t t h e tri gg er f o r t h e produ cti on o f L H, wh i ch m ed iates a nd r og e n s yn t h esis . I n c on trast t o G n R H a n al og s , dega r e li x does no t c a u se t u m o r fl a r e s y m p t o ms sec ond ar y t o tem por ar y i nc r eased and r ogen p r odu cti on. A la r g e ra ndo mize d cli n ical tr ial d em on st ra t ed t ha t dega r e li x was ass o ciate d wit h a ra p i d a nd s u stai n e d r e du cti on i n se r u m t es t os t e r on e , p r o state-s p ecific a n ti g e n (PSA) , FSH , a nd LH le v el s, w it h a l oad i ng dos e o f 240 m g s ub c u ta n e ou sl y , f o ll o we d by a m on t h l y m a i n t enance dose o f 80 m wit h c o m p ara b le e f ficac y t o le upro li de . T he m os t co mmo n si d e e f fects ( g reater t h a n 10 %) were hot f las h es and pa i n a t t he i n j ec ti on sit e w h e n p atie n ts were p r ov i d e d d e g a r elix f o r a 12 -m on t h pe rio d. It is unkno w n if d e g areli x will h a v e a simila r ch r on i c s i de e f f ec t p r o file kno w n t o b e ass o ciate d wit h l ong -ter m Gn R H a na l og use. | 6 | 0.005 | 0.03 | 0.07 | 0.09 | 0.06 | 0.005 | 0.09 | 4 |
20,106 | G O NADOTRO P IN-RELEASING HOR MO NE AN T AGO N ISTS | Pharmacology | null | nan nan | Th e r ec o mm ended l oad i ng do se o f d e g areli x is 240 m g, a d mi n istere d as t wo i n je c ti ons o f 120 m g each s ub c u ta n e ou sl y . M on t h l y mai n te n a n ce doses of 80 m g as a 20 m g /mL so l u ti on is starte d 28 d a y s after t h e l o a d i ng do se . In a n a na l ys i s o f pha rm acok i n etic/ ph armac odyn amic (PK/PD) p r op ertie s o f d e g a r elix i n 60 hea lt hy m a l es, after a si ng le s ub c u ta n e ou s do se , a termi nal h al f li f e of 47 days was obse r v e d . PK p r op erties o f d e g areli x h a v e b ee n e v al u ate d when ad mi n i s t e r ed a s a s ub c u ta n e ou s d e po t o f d r ug as a g el i n six d i f f e r e n t doses t o 48 hea lt hy m ales a nd w h e n a d mi n istere d i n tra v e nou sl y . U si ng d at a fr o m seve r a l c li n i c al trials , t h e rate o f d r ug d i f f u si on fr o m s ub c u ta neous ad mi n i s tr a ti on res u lts i n d etecta b le d r ug up t o 60 d a y s aft e r a si ng le dose co m pa r ed t o l ess t h a n 4 d a y s w h e n t h e d r ug is i n jecte d i n t r a v e nous l y . | 6 | 0.05 | 0.09 | 0.03 | 0.01 | 0.05 | 0.01 | 0.09 | 2 |
20,107 | ANTIANDR OGE NS | Pharmacology | null | nan nan | Fl u tami de i s a pu r e an ti and r og e n wit h no i n tri n sic ster o i d al acti v it y . | 6 | 0.09 | 0.1 | 0.08 | 0.075 | 0.06 | 0.04 | 0.1 | 2 |
20,108 | ANTIANDR OGE NS | Pharmacology | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,109 | ANTIANDR OGE NS | Pharmacology | nan nan | Fl u tami de ’ s m echan i s m o f ac ti on is as a n a nd r og e n -rece p t o r a n t a gon ist . Th is b i nd i ng p r even t s d i hyd r o test o ster on e b i nd i ng a nd s ub se qu e n t t r a n sl o cati on o f t he and r ogen -rece p t o r c o m p le x i n t o t h e nu clei o f cells . Beca u se it i s a pu r e an ti and r og e n, it acts on l y at t h e cell u lar le v el . T h e a d mi n is t r a ti on o f fl u t a mi de a l on e lea d s t o i n crease d LH a nd FSH produ cti on and a conco mit an t i n crease i n p lasma test o ster on e a nd E 2 le vels. Plasma p r o t e i n b i nd i ng r anges b etwee n 94 % a nd 96 % f o r fl u tami d e a nd b et w ee n 92 % and 94 % f o r 2 - hyd r oxy fl u tami d e , its maj o r meta bo lite . W hen t h e drug i s ad mi n i s t e r ed t h r ee times a d a y , stea dy state le v els are ac h ie v e d by d a y 6. T he e limi na ti on ha lf-life at stea dy state is 7.8 hou rs , a nd 2 - hydroxyf l u t a mi de ach i eves c o n ce n trati on s 50 times h i gh er t h a n t h e p are nt drug at s t eady s t a t e and has equ al o r g reater po te n c y t h a n t h at o f f l u tami d e T he e limi na ti on half-life f o r t h e meta bo lite is 9.6 hou rs . T he h i gh p la s m a concen tr a ti ons o f 2 - hyd r oxy fl u tami d e , as c o m p are d wit h | 6 | 0.01 | 0.03 | 0.02 | 0.01 | 0.01 | 0.02 | 0.03 | 2 |
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20,110 | ANTIANDR OGE NS | Pharmacology | nan nan | f l u tami d e , sugges t t ha t t he t h era p e u tic b e n efits o f fl u tami d e are me d iate d pr ima r il y t h r ough it s ac ti ve meta bo lite . | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,111 | ANTIANDR OGE NS | Bicalutamide | null | nan nan | Bical u tami de i s ano t he r nons t e r o i d al a n tia nd r og e n t h at h as b ee n a pp r oved by t h e F DA f o r use i n t he Uni te d States . T h e rec o mme nd e d do se is on e 50 -m g ta b l e t pe r da y . One r andom ize d trial re po rte d t h at b ical u tami d e c o m p a red f avo r ab l y w it h fl u t a mi d e i n p atie n ts wit h a dv a n ce d p r o state ca n ce r . B i ca l u t a mi de appear s t o b e relati v el y well t o lerate d a nd is ass o ciate d w it h a l owe r i nc i d e n ce o f d iarr h ea t h a n is fl u tami d e . | 6 | 0.098 | 0.1 | 0.073 | 0.062 | 0.048 | 0.098 | 0.1 | 2 |
20,112 | NOVEL ANTIANDR OGE NS | null | null | nan nan | NOVEL ANTIANDR OGE NS | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,113 | NOVEL ANTIANDR OGE NS | Abirate r one Acetate | null | nan nan | Af te r t he f a il u r e o f i n iti a l and r og e n ma n i pu lati on wit h G n RH a n al og s a nd p e r i ph e ra l an ti and r ogens, p r os tate ca n cer c on ti nu es t o res pond t o a v ariet y of sec on d- and t h ir d -li ne ho r mon al i n ter v e n ti on s . Base d on t h is ob ser v ati on, C YP17, a key enzy m e i n and r og e n a nd estr og e n s yn t h esis , was tar g ete d u si ng k e toconazo l e, wh i ch i s a wea k, re v ersi b le , a nd non s p ecific i nh i b it o r of C Y P 17 r esu lti ng i n m odes t a n tit u m o r acti v it y o f s ho rt du ra b ilit y . M o r e r ece n tl y , ab ir a t e r one, a m o r e po te n t (i . e ., 20 times m o re t h a n k et o c on az ole ) , selecti ve, and irr eve r s i b l e i nh i b it o r o f CYP 17, h as b ee n i nv esti g ate d i n cast r ati on -r ecu rr en t p r os t a t e c a n ce r , a nd si gn ifica n t ob jecti v e res pon ses h a v e b e en obse r ved Che mi c all y , it is a 3 - py ri dy l ster o i d p re gn e no l one– d e r i v e d co m pound ava il ab l e i n a n o ral p r od r ug f o rm o f a b irater on e acet ate. I ts mai n t ox i c it y i s fr o m sy m p t o ms o f mi n eral o c o rtic o i d e x cess (i n cl ud i ng hypok al e mi a, hype rt ens i on, and fl u i d ov erl o a d ) , b eca u se c on ti nuou s CYP 17 | 6 | 0.005 | 0.04 | 0.01 | 0 | 0 | 0 | 0.04 | 2 |
20,114 | NOVEL ANTIANDR OGE NS | Enzalutamide | null | nan nan | Enzalutamide | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,115 | NOVEL ANTIANDR OGE NS | Enzalutamide | null | nan nan | En zal u t a mi de i s a new d i a r y lt h i ohyd a n t o i n c o m pound t h at b i nd s AR wit h a n a f f i n i ty t ha t i s seve r a l-f o l d g reater t h a n t h e a n tia nd r og e n s b ical u tami de a nd f l u t a mi de. T h i s c l ass o f nov el AR i nh i b it o r als o d isr up ts t h e nu clear t r a n sl o cati on o f AR and im pa irs DNA b i nd i ng t o a nd r og e n res pon se eleme n ts and t he r ec r u itm en t of c o acti v at o rs . I n earl y cli n ical trials , pro misi ng r esu lt s have been ob ser v e d i n castrate refract o r y a nd c h em o t he r apy -r es i s t an t se tti ng s . T h e maj o r meta bo lite o f e n zal u tami d e i s N-d esmet hy l enza l u t a mi de, a n d CYP 2 C 8 is res pon si b le f o r t h e f o rmati on o f t h e activ e m e t abo lit e, N - des met hy l e n zal u tami d e . E n zal u tami d e ph a r ma cok i ne ti cs, i n t he s t udi e d do se ra ng e b etwee n 30 m g t o 480 m g, e xh i b ite d a li nea r , t wo - co m pa rtme n tal m od el wit h first- o r d er k i n etics . I n | 6 | 0.005 | 0.01 | 0.07 | 0.01 | 0.005 | 0.01 | 0.07 | 3 |
20,116 | NOVEL ANTIANDR OGE NS | Galete r one and Orte r onel | null | nan nan | Nov el CYP 17 i nh i b it o r s t ha t are m o re selecti v e f o r 17,20 -l y ase ov er 17 α- hydroxylase a r e cu rr en tl y be i ng d e v el op e d. Orter on el ( T AK- 700 ) is a n e x am p le o f a h i gh l y se l ec ti ve 17,20 l y ase , w h ic h is c u rre n tl y und e r go i ng ph ase III c li n i ca l tri a l s i n a p r e - a nd po stc h em o t h era py castrate-rec u rre nt setti ng a f t e r t he f a il u r e o f androg e n - d e p ri v ati on t h era p y . Ot h er nov el a g e n ts be i ng deve l oped i nc l ud e g aleter on e , w h ic h is a n i nh i b it o r o f CYP 17 α-hydro x y l ase and C17,20 l y ase . S u r v i v al mec h a n isms o f p r o state ca n cer cells ta r ge t ed by ga l e t e r one incl ud e its b i nd i ng t o AR , c o m p etiti v e i nh i b iti o n o f t es t os t e r one b i nd i ng, a nd a re du cti on i n t h e qu a n tit y o f AR pro tei n wit h i n t he p r os t a t e can cer cells . It ca n als o e nh a n ce t h e d e g ra d ati on of c on stit u ti ve l y ac ti ve sp li ce v aria n ts . T h eref o re , ta k e n t og et h e r , it d imi n is hes t he ab ilit y o f t he c ells t o res pond t o t h e l o w le v els o f a nd r ogenic grow t h s i gna l s. T h i s agen t i s cu rre n tl y i n earl y cli n ical safet y a nd e f fica cy testi ng fo r advanced s t age p r o state ca n ce r . | 6 | 0.095 | 0.08 | 0.06 | 0.04 | 0.03 | 0.02 | 0.095 | 1 |
20,117 | O THE R S E X STEROID T HERAPI E S | null | null | nan nan | O THE R S E X STEROID T HERAPI E S | 6 | 0.05 | 0.07 | 0.08 | 0.09 | 0.1 | 0.1 | 0.1 | 5 |
20,118 | O THE R S E X STEROID T HERAPI E S | Fluoxymeste r one | null | nan nan | Fl uoxy m es t e r one i s an and r og e n t h at h as b ee n u se d i n w o me n wit h metastati c b r eas t cance r who h a v e ho rm on all y res pon si v e ca n cers a nd w ho h a v e prog r essed on o t he r ho rm on al t h era p ies s u c h as tam ox ife n, a n a ro matas e i nh i b it o r , o r m eges tr o l acetate . T h e u s u al do se is 10 m g g i v e n t w ice d a i l y . A lt hough t he ove rall res pon se rate is l o w f o r fl uoxy mester one u se d i n t h i s c li n i ca l s it ua ti on , t h ere are s o me p atie n ts w ho h a v e s ub sta n ti a l an tit u m o r r espons es lasti ng f o r m on t h s o r e v e n y ears . T ox i c iti es assoc i a t ed w it h fl uoxy mester on e are t ho se t h at w ou l d b e e xp ecte d w it h an and r ogen : h irs u tism , male- p atter n b al dn ess , vo ice l ow e r i n g ( hoa r seness ) , acne, e nh a n ce d li b i do, a nd er y t h r o c y t o sis . Fl uoxy m es t e r one can a l so ca use ele v ate d li v er f un cti on test res u lts i n s ome p atie n ts a nd, r a r e l y , has been a ss o ciate d wit h h e p atic n e op lasms . | 6 | 0.005 | 0.02 | 0.03 | 0.04 | 0.06 | 0.01 | 0.06 | 5 |
20,119 | O THE R S E X STEROID T HERAPI E S | Pharmacology | null | nan nan | Pharmacology | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,120 | O THE R S E X STEROID T HERAPI E S | Est r ogens: Diethylstilbest r ol and Estradiol | null | nan nan | Est r ogens: Diethylstilbest r ol and Estradiol | 6 | 0.05 | 0.01 | 0.02 | 0.01 | 0.01 | 0.01 | 0.05 | 1 |
20,121 | O THE R S E X STEROID T HERAPI E S | Est r ogens: Diethylstilbest r ol and Estradiol | null | nan nan | D iet hy lstil bes tr o l ( D ES) had bee n t h e p rimar y ho rm on al t h era py f o r po stme nopausa l m e t as t a ti c b reast ca n ce r . Ra ndo mize d c o m p arati v e trial s d em on st ra t ed it had a s imil a r res pon se rate t o t h at o f tam ox ife n . | 6 | 0.09 | 0.01 | 0.08 | 0.02 | 0.075 | 0.03 | 0.09 | 1 |
20,122 | O THE R S E X STEROID T HERAPI E S | Est r ogens: Diethylstilbest r ol and Estradiol | nan nan | How e v e r , based on t hese tri a ls , DES u se was s upp la n te d by tam ox ife n, pr ima r il y because D ES has m o re t ox icit y . DES is o ccasi on all y u se d i n metastati c b r eas t cance r pa ti en ts w ho h a v e ho rm on all y se n siti v e ca n cers | 6 | 0.09 | 0.01 | 0.08 | 0.02 | 0.075 | 0.03 | 0.09 | 1 |
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20,123 | O THE R S E X STEROID T HERAPI E S | Est r ogens: Diethylstilbest r ol and Estradiol | nan nan | t h at h a ve f a il ed t o r espond t o m u lti p le o t h er ho rm on al t h era p ies . T h e u su al do se i n t h i s s it ua ti on i s 15 mg p er d a y , eit h er as a si ng le do se o r as d i v i ded do ses . D ES was a l so used as a nd r og e n a b lati on t h era py i n me n wit h metastati c p r os t a t e cance r D o ses o f a pp r ox imatel y 3 m g p er d a y res u l t in test o ste rone l eve l s t ha t a r e se e n i n a n a no rc h i d state . DES tox i c iti es i nc l ude nau sea a nd vo miti ng, b reast te nd er n ess , a nd a d a rk e n i ng o f t he n i pp l e–a r eo l a r c o m p le x. DES i n creases t h e ris k o f t hro m boe m bo li c pheno m enon, w h ic h ma y res u lt i n life-t h reate n i ng c o m p lic a ti ons. A lt hough D E S is no t cli n icall y a v aila b le i n t h e U n ite d States , simil a r an tit u m o r e f f ec ts a nd t ox icities are see n wit h estra d i o l , w ith a ta r g et dose o f 10 m g by m ou t h t h ree times a d a y . T h e ph armac o l ogy o f E 2 h as b ee n ex t ens i ve l y desc ri bed elsew h ere . | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
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20,124 | O THE R S E X STEROID T HERAPI E S | Med r oxyp r ogeste r one and Megest r ol | null | nan nan | Med r oxyp r ogeste r one and Megest r ol | 6 | 0.05 | 0.09 | 0.01 | 0.08 | 0.07 | 0.06 | 0.09 | 2 |
20,125 | O THE R S E X STEROID T HERAPI E S | Med r oxyp r ogeste r one and Megest r ol | null | nan nan | Me droxyp r oges t e r one and me g estr o l are 17 -OH- p r og ester on e d eri v ati v e s d i f f e r i ng i n a doub l e bond be t w ee n C 6 a nd C 7 po siti on s i n me g estr o l . H ist or ic a ll y , m eges tr o l was u se d as a ho rm on al a g e n t f o r p atie n ts wit h a dv a n ce d b r eas t cance r , usua l ly at a t o tal d ail y do se o f 160 m g. Add iti ona ll y , it i s s till used f o r t h e treatme n t o f ho rm on all y res pon si v e metastati c endo m e tri a l cance r , at a do se o f 320 m g p er d a y . I n a dd iti on, do ses of 160 m g pe r day a r e o ccasi on all y u se d as a ho rm on al t h era py f or pro state cance r Meges tr o l h as als o b ee n e x te n si v el y e v al u ate d f o r t h e t r eatme n t o f ano r ex i a / cachex ia relate d t o ca n cer o r AIDS . – V ari ou s do sa g es r ang i ng fr o m 160 t o 1,600 m g p er d a y h a v e b ee n u se d. A pro s p ecti ve s t udy has de m on strate d a do se – res pon se relati on s h i p wit h d o ses up t o 800 m g pe r da y . L ow d o sa g es o f me g estr o l ( 20 t o 40 m g p er d a y ) h a v e b e en shown t o be an e f fecti v e mea n s o f re du ci ng ho t flas h es i n w omen w it h br e as t cance r and i n m en w ho h a v e und e r gon e a nd r og e n a b lati on t h e r a p y A lt hough m eges tr o l h a d h ist o ricall y b ee n c o mm on l y a d mi n ister ed four tim es pe r da y , t he l ong termi n al h alf-life s uppo rts on ce- p e r - d a y do s ing. Me ges tr o l i s a r e l a ti ve l y we ll-t o lerate d me d icati on, wit h its m o st pro mi n e n t s i de e f f ec t s be i ng app etite stim u lati on a nd res u lta n t wei gh t gain. | 6 | 0.005 | 0.09 | 0.01 | 0 | 0 | 0 | 0.09 | 2 |
20,126 | O THE R S E X STEROID T HERAPI E S | Med r oxyp r ogeste r one and Megest r ol | null | nan nan | A lt hough t hese m ay be bene ficial e f fects i n p atie n ts wit h a no re x ia/cac h e xia, t h e y ca n be im po rt an t p r ob l em s i n p atie n ts wit h b reast o r e ndo metrial ca n ce r s . Ano t he r s i de e f f ec t o f me g estr o l acetate is t h e mar k e d s upp ress ion of a dr e na l s t e r o i d p r oduc ti on by s upp ressi on o f t h e p it u itar y– a d re n al a x is . | 6 | 0.05 | 0.01 | 0.02 | 0.01 | 0.01 | 0.01 | 0.05 | 1 |
20,127 | O THE R S E X STEROID T HERAPI E S | Med r oxyp r ogeste r one and Megest r ol | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,128 | O THE R S E X STEROID T HERAPI E S | Med r oxyp r ogeste r one and Megest r ol | nan nan | A lt hough t h i s appea r s t o be a s y m p t o matic i n t h e maj o rit y o f p atie n ts , r e por ts sugges t t ha t t h i s ad r en al s upp ressi on ca n ca u se cli n ical p r ob lems in s o me p ati en t s . T h i s d r ug ha s b ee n a b r up tl y st opp e d f o r d eca d es wit hout t h e r ec o g n iti on o f un t owa r d s e qu elae i n p atie n ts , a nd it seems reas on a b le to c on ti nue t h i s p r ac ti ce. None t h eless , if A dd is on ia n si gn s o r s y m p t o ms d e v el op a ft e r d r ug d i scon ti nu ati on, c o rtic o ster o i d s s hou l d b e a d mi n ister ed. F ur t h e rmo r e, if pa ti en t s who r ecei v e me g estr o l h a v e a si gn ifica n t i n fecti on, e xp e r ien ce tr au m a, o r unde r go s u r g er y , t h e n c o rtic o ster o i d c ov era g e s hould b e a d mi n i s t e r ed. T he r e appear s t o b e a sli gh tl y i n crease d i n ci d e n ce o f t hro m boe m bo li c pheno m ena i n p atie n ts recei v i ng me g estr o l al on e . T his r is k a pp e a r s t o be h i ghe r if me g estr o l is a d mi n istere d wit h c on c o mita n t c y t o t ox i c t he r ap y . T he r e a re c on flicti ng re po rts re g ar d i ng me g estr o l-ca u si ng ede m a . If it does, t h e e d ema is g e n erall y mi n imal a nd easil y h a nd le d w it h a mil d d i u r e ti c. Me g estr o l ma y ca u se im po te n ce i n s o me me n T he i nc i dence o f t h i s is c on tr ov ersial , alt hough it is g e n erall y a greed t h at t h is i s a r eve r s i b l e s it ua ti on. Me g estr o l ca n ca u se me n str u al i rr e gu la r iti es, t he m os t p r o mine n t o f w h ic h is wit hd rawal me n str u al b lee d i ng w it h i n a f ew weeks o f d r ug d isc on ti nu ati on . Alt hough n a u sea a nd vo miti n g have so m e tim es bee n attri bu te d as a t ox icit y o f t h is d r ug, t h ere a r e d ata t o de m ons tr a t e t ha t t h i s d r ug h as a n tiemetic p r op erties . I n te rms of ma gn it ude, m eges tr o l appea rs t o d ecrease bo t h n a u sea a nd vo miti ng i n a dv a n ce d - s t age cance r pa ti en ts by a pp r ox imatel y tw o t h ir d s . Me d r oxyp r oges t e r one has ma ny o f t h e same p r op erties , cli n ical u ses , a nd t ox i c iti es as m eges tr o l ac etate . It h as n e v er b ee n c o mm on l y u se d i n the Un ite d St a t es f o r t he tr ea tm en t o f b reast ca n cer bu t h as b ee n u se d m o re i n Europ e . M ed r oxyp r oges t e r on e is a v aila b le i n 2.5 - a nd 10 -m g ta b lets a nd in i n jecta ble f o rm u l a ti ons o f 10 0 a nd 400 m g /L . D o si ng f o r t h e treatme n t o f metastati c b r eas t o r p r os t a t e can cer h as c o mm on l y b ee n 400 m g p er wee k | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
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20,129 | O THE R S E X STEROID T HERAPI E S | Med r oxyp r ogeste r one and Megest r ol | nan nan | or m or e a nd 1,000 m g pe r week o r m o re f o r metastatic e ndo metrial ca n c e r . In jecta b l e o r da il y o r a l doses ha v e b ee n u se d f o r c on tr o lli ng ho t flas h es . | 6 | 0.095 | 0.87005 | 0.62005 | 0.43075 | 0.37005 | 0.025 | 0.87005 | 2 |
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20,130 | O THE R S E X STEROID T HERAPI E S | Pharmacology | null | nan nan | Pharmacology | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,131 | O THE R S E X STEROID T HERAPI E S | Pharmacology | null | nan nan | Th e e x act m echan i s m o f an tit u m o r effect o f me d r oxyp r og ester on e a nd me g est ro l i s unc l ea r . T hese d r ug s h a v e b ee n re po rte d t o s upp ress a d re n a l ste ro i d sy n t hes i s supp r ess E R le v els , alter t u m o r ho rm on e meta bo li s m , enhance s t e r o i d meta bo lism , a nd d irectl y k ill t u m o r cells I n add iti on, p r oges ti n s ma y i n fl u e n ce s o me g r o wt h fact o rs , | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,132 | O THE R S E X STEROID T HERAPI E S | Pharmacology | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,133 | O THE R S E X STEROID T HERAPI E S | Pharmacology | nan nan | s uppr es s p l as m a es tr one su lf at e f o rmati on, a nd, at h i gh c on ce n trati on s , i nh i b it P - g l ycop r o t e i n. Th e o r a l b i oava il ab ilit y o f t h ese p r og estati on al a g e n ts is unkno w n, alt hough abso r p ti on appea r s to b e poo r f o r me d r oxyp r og ester on e relati v e to me g est ro l . Th e t e rmi na l ha lf-lif e f o r me g estr o l is a pp r ox imatel y 14 hou rs , with a t max of 2 t o 5 hou r s a ft e r o r a l i ng esti on . T h e AUC f o r a si ng le me g estr ol do se of 160 m g i s be t ween 2. 5- a nd 8 -f o l d h i gh er t h a n t h at f o r si ng le- dose me droxyp r oges t e r one a t 1,000 m g wit h a ra d i o acti v e do se o f me g estr o l; 50% t o 78 % i s f ound i n t he u ri n e after o ral a d mi n istrati on, a nd 8 % t o 30 % is found i n t he f eces. Meta bo li s m and exc r e ti on o f me d r oxyp r og ester on e h a v e b ee n i n c o m p l e t e l y cha r ac t e ri zed. I n hu ma n s , 20 % t o 50 % o f a [ 3 H] me d r oxyp r oges t e r one do se is e x crete d i n t h e u ri n e a nd 5 % t o 10 % i n t h e st ool a ft e r i n tr avenous adm i n istrati on Meta bo lism o f me droxyp r oges t e r one occu r s v ia hyd r oxy lati on, re du cti on, d emet hy lati on, a nd c omb i na ti ons o f t hese r ea cti on s . T h e maj o r u ri n ar y meta bo lite is a g l u c uron i de. L ess t han 3 % o f t h e do se is e x crete d as un c on j ug ate d me droxyp r oges t e r one i n hu ma n s . Cleara n ce o f me d r oxyp r og ester on e h a s b ee n r ep o rt ed t o r ange be t we e n 27 a nd 70 L p er hou r . T h e i n itial vo l ume of d ist r i bu ti on i s be t ween 4 and 8 L i n hu ma n s . T h e mea n termi n al h alf- li f e is 60 ho ur s. T he t m ax f o r m ed r oxyp r og ester on e o cc u rs 2 t o 5 hou rs after o r al a d mi n is t r a ti on. Med r oxyp r og ester on e a pp ears t o b e c on ce n trate d i n t h e | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
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20,134 | O THE R S E X STEROID T HERAPI E S | Pharmacology | nan nan | small i n t es ti ne, t he co l on, and i n a d i po se tiss u e i n hu ma n a u t op s y st ud ie s . | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,135 | O THE R S E X STEROID T HERAPI E S | Pharmacology | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,136 | O THE R S E X STEROID T HERAPI E S | Pharmacology | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,137 | O THE R S E X STEROID T HERAPI E S | Pharmacology | nan nan | Me droxyp r oges t e r one m ay r edu ce t h e c on ce n trati on o f t h e N - d esmet hy lt a m ox if en m e t abo lite c on ce n trati on. Pr og estati on al a g e n ts als o ma y i n cr ease p l as m a wa rf a ri n le v els . T h ese re po rts are c on siste n t with C YP3A be i ng t he s it e o f i n t e racti on. | 6 | 0.05 | 0.01 | 0.02 | 0.01 | 0.01 | 0.01 | 0.05 | 1 |
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20,138 | O THE R HOR MO NAL TH E RAPIES | null | null | nan nan | O THE R HOR MO NAL TH E RAPIES | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,139 | O THE R HOR MO NAL TH E RAPIES | Oct r eotide | null | nan nan | Oct r eotide | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,140 | O THE R HOR MO NAL TH E RAPIES | Pharmacology | null | nan nan | O ct r e o ti de i s an 8 - a mi no ac i d s yn t h etic a n al og o f t h e 14 -ami no aci d p e ptide s o mat o st a ti n . Oc tr eo ti de ha s a similar h i gh affi n it y f o r s o mat o stati n r ece p t ors, as does it s pa r en t co m pound, wit h a c on ce n trati on t h at i nh i b it s | 6 | 0.09 | 0.075 | 0.06 | 0.03 | 0.025 | 0.01 | 0.09 | 1 |
20,141 | O THE R HOR MO NAL TH E RAPIES | Pharmacology | null | nan nan | t h e r ece p t o r by 50 % i n t he su b n a no m o lar ra ng e . Octre o ti d e i nh i b its i n s ulin, g l u ca gon, panc r ea ti c po l ypep ti d e , g astric i nh i b it o r y po l yp e p ti d e , a nd g a st r in sec r eti on. It has a m uch l onge r du rati on o f acti on t h a n t h e p are n t c o m pound b eca u se o f it s g r ea t e r r es i s t an ce t o e n z y matic d e g ra d ati on. Its a b s o r p ti on a f te r s ubcu t aneous ad mi n i s tr at i on is ra p i d, a nd b i o a v aila b ilit y is 100 % a fte r s ub c u ta neous i n j ec ti on. P eak c on ce n trati on s o f 4 μg /L after a 100 - μg dose o cc ur wi t h i n 20 t o 30 mi nu t es o f s ub c u ta n e ou s i n jecti on a nd are 20 % t o 40% of the co rr espond i ng i n tra v e nou s i n jecti on. B o t h p ea k c on ce n trati on a nd AUC f o r oc tr eo ti de i nc r e ase li n earl y wit h do se . T h e t o tal body clea r a n c e i n hea lt hy vo l un t ee rs is 9.6 L p er hou r . He p atic meta bo lism o f o ct r e o ti de accoun t s f o r 30 % t o 40 % o f t h e d r ug ’ s d is po siti on, a nd 1 1 % t o 20% is exc r e t ed unchanged i n t h e u ri n e . T h e vo l u me o f d istri bu ti on ra nges b et w ee n 18 and 30 L , and t he termi n al h alf-life is re po rte d t o b e b etween 72 a nd 98 mi nu t es. Si x t y -fi ve pe rce n t o f t h e d r ug is p r o tei n bound p rimaril y to t h e li pop r o t e i n fr ac ti on . Beca u se o f t h e s ho rt h alf-life , classic o ct r e o ti de i s ad mi n i s t e r ed sub c u ta n e ou sl y tw o o r t h ree times p er d a y . A sl ow-r el ease f o rm o f oc tr eo ti d e , d esi gn e d f o r on ce- p er-m on t h a d mi n is t r a ti on, con tr o l s t he sy m p t o ms o f carci no i d s ynd r o me at least as w ell as t h r ee -tim es - pe r - day oc tre o ti d e . | 6 | 0.05 | 0.01 | 0 | 0 | 0 | 0 | 0.05 | 1 |
20,142 | O THE R HOR MO NAL TH E RAPIES | Pharmacology | null | nan nan | Fisher B, Costantino J P , W ickerham DL, et al. T amoxifen for the prevention of breast cancer: current status of the National Su r gical Adjuvant Breast and Bowel Project P-1 stud y . J Natl Cancer Inst 2005;97:1652–1662. Fisher B, Dignam J, W olmark N, et al. T amoxifen in treatment of intraductal breast cancer: National Su r gical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993–2000. Colleoni M, Gelber S, Goldhirsch A, et al. T amoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group T rial 13-93. J Clin Oncol 2006;24:1332–1341. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: A TLAS, a randomised trial. Lancet 2013;381:805–816. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347–352. | 6 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 1 |
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20,147 | O THE R HOR MO NAL TH E RAPIES | Pharmacology | null | nan nan | Biochem 1990;36:659–666. Ingle JN, Ahmann DL, Green SJ, et al. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cance r . N Engl J Med 1981;304:16–21. Stewart HJ, Forrest A P , Gunn JM, et al. The tamoxifen trial - a double-blind comparison with stilboestrol in postmenopausal women with advanced breast cance r . Eur J Cancer 1980;Suppl 1:83– 88. Byar D P . Proceedings: The V eterans Administration Cooperative Urological Research Group ’ s studies of cancer of the prostate. Cancer 1973;32: 1 126– 1 130. Loose-Mitchell DS, Stancel GM. Est r ogens and P r ogestin s . 10 ed. New Y ork: McGraw-Hill; 2001. Bonomi P , Pessis D, Bunting N, et al. Megestrol acetate used as primary hormonal therapy in stage D prostatic cance r . Semin Oncol 1985;12:36–39. Bruera E, Macmillan K, Kuehn N, et al. A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cance r . Cancer 1990;66:1279–1282. Feliu J, Gonzalez-Baron M, Berrocal A, et al. Usefulness of megestrol acetate in cancer cachexia and anorexia. A placebo-controlled stud y . Am J Clin Oncol 1992;15:436–440. Loprinzi CL, Ellison NM, Schaid DJ, et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 1990;82: 1 127– 1 132. T chekmedyian NS, Hickman M, Siau J, et al. Megestrol acetate in cancer anorexia and weight loss. Cancer 1992;69:1268–1274. Loprinzi CL, Michalak JC, Schaid DJ, et al. Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J Clin Oncol 1993; 1 1:762–767. Loprinzi CL, Jensen MD, Jiang NS, et al. Effect of megestrol acetate on the human pituitary-adrenal axis. Mayo Clin P r oc 1992;67: 1 160– 1 162. Leinung MC, Liporace R, Miller CH. Induction of adrenal suppression by megestrol acetate in patients with AIDS. Ann Intern Med 1995;122:843–845. Rowland KM J r ., Loprinzi CL, Shaw EG, et al. Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer T reatment Group stud y . J Clin Oncol 1996;14:135–141. Loprinzi CL, Johnson P A, Jensen M. Megestrol acetate for anorexia and cachexia. Oncology 1992;49:46–49. V on Roenn JH, Armstrong D, Kotler D P , et al. Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med 1994;121:393–399. Alexieva-Figusch J, Blankenstein MA, Hop WC, et al. T reatment of metastatic breast cancer patients with di f ferent dosages of megestrol acetate; dose relations, metabolic and endocrine e f fects. Eur J Cancer Clin Oncol 1984;20:33–40. T seng L, Gurpide E. E f fects of progestins on estradiol receptor levels in human endometrium. J Clin Endocrinol Metab 1975;41:402–404. Gurpide E, T seng L, Gusbe r g SB. Estrogen metabolism in normal and neoplastic endometrium. Am J Obstet Gynecol 1977;129:809–816. Gordon GG, Altman K, Southren AL, et al. Human hepatic testosterone A-ring reductase activity: e f fect of medroxyprogesterone acetate. J Clin Endocrinol Metab 1971;32:457–461. Allegra JC, Kiefer SM. Mechanisms of action of progestational agents. Semin Oncol 1985;12:3–5. Ewing TM, Murphy LJ, Ng ML, et al. Regulation of epidermal growth factor receptor by progestins and glucocorticoids in human breast cancer cell lines. Int J Cancer 1989;44:744–752. | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
20,148 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | null | null | nan nan | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | 6 | 0.05 | 0.07 | 0.08 | 0.09 | 0.1 | 0.1 | 0.1 | 5 |
20,149 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Angiogenic Switch and Regulatory P r oteins | null | nan nan | Angiogenic Switch and Regulatory P r oteins | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,150 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Angiogenic Switch and Regulatory P r oteins | null | nan nan | T u m or deve l op m en t and p r ogr essi on d e p e nd on a ng i og e n esis . Recr u itm ent of n e w b l ood vesse l s t o t he t umo r site is re qu ire d f o r t h e d eli v er y o f nu t r ie n t s and oxygen t o t he c a n cer ou s g r o wt h s a nd f o r t h e rem ov al o f wa ste produ ct s. Cance r ce ll s p r o m o te a ng i og e n esis at a n earl y sta g e o f t u m or i g e nes i s, beg i nn i ng w it h t h e release o f m o lec u les t h at se nd si gn als to t h e s urround i ng no rm a l hos t t i ss u e a nd stim u late t h e mi g rati on o f mic rov a scu l a r endo t he li a l ce l l s (EC) i n t h e d irecti on o f t h e a ng i og e n ic stim u l u s . T hese ang i ogen i c f ac t o rs no t on l y me d iate EC mi g rati on, bu t a lso E C pro l i f e r a ti on and mi c r ove ssel f o rmati on i n t u m o rs und er go i ng t h e s w itc h to t he ang i ogen i c pheno t yp e . E xp erime n tal e v i d e n ce f o r t h is ang i og e n i c sw it ch was obse r v e d w h e n hyp er p lastic islets i n tra n s g e n ic mice ( R I P - T a g m ode l) sw it ch fr o m small ( <1 mm) , w h ite micr o sc op ic do rma nt t u m or s t o r ed, r ap i d l y g r ow i ng t u m o rs . D o rma n t t u m o rs h a v e b ee n d isc ov e red du ri ng au t ops i es of i nd i v i du als w ho d ie d o f ca u ses o t h er t h a n ca n ce r . T hese au t opsy s t ud i e s s ugg est t h at t h e v ast maj o rit y o f micr o sc opic i n sit u ca nce r s neve r sw it ch t o t h e a ng i og e n ic ph e no t yp e du ri ng a no rma l li f etime . S uch i nc i p i en t t u m o rs are u s u all y no t n e ov asc u larize d a nd ca n r emai n ha rml ess t o t he hos t f o r l ong p eri od s o f time as micr o sc op ic lesi ons t h at a r e in a s t a t e o f do rm anc y T h ese non a ng i og e n ic t u m o rs ca nno t e xp a nd beyond t he i n iti a l mi c r o sc op ic size a nd ca nno t b ec o me cli n icall y d etecta b l e, l e t ha l t u m o r s un til t h e y h a v e switc h e d t o t h e a ng i og e n ic | 6 | 0.05 | 0.075 | 0.09 | 0.08 | 0.06 | 0.04 | 0.09 | 3 |
20,151 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Angiogenic Switch and Regulatory P r oteins | null | nan nan | ph e no t ype t h r ough neova sc u larizati on a nd / o r b l ood v essel c oop ti on . | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,152 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Angiogenic Switch and Regulatory P r oteins | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.1 | 0.095 | 0.1 | 5 |
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20,153 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Angiogenic Switch and Regulatory P r oteins | nan nan | D e p e nd in g on t he t u m o r t ype a nd t h e e nv ir on me n t , t h is switc h ca n o cc u r at d i f f e r e n t s t ages o f t he t u m o r p r og ressi on p at h wa y a nd u ltimatel y d e p e nds on a n et ba l ance o f pos iti ve and n e g ati v e re gu lat o rs . T hu s , t h e a ng i og e n ic ph e no t ype m ay r esu lt fr o m t h e p r odu cti on o f g r o wt h fact o rs by t u m o r c ells a nd / or t he down r egu l a ti on o f n e g ati v e m odu lat o rs . C h a nges i n t h i s ang i ogen ic b ala n ce affecti ng t h e le v els o f acti v at o r a nd i nh i b it or m o l ecu l es d i c t a t e wh et h er a n EC will b e i n a qu iesce n t o r a n a ng i og e n i c s t a t e. No rm a ll y , t h e i nh i b it o rs p re do mi n ate , t h ere by b l o c k i ng grow t h. Once t he ba l ance sh i f ts i n fa vo r o f t h e a ng i og e n ic state , pro a ng i ogen i c f ac t o r s p r o m p t s t h e acti v ati on, g r o wt h, a nd d i v isi on o f v asc u la r E Cs, r esu lti ng i n t he f o rmati on o f n ew b l ood v essels . Acti v ate d E Cs produce and r e l ease m a tr ix metall op r o tei n ases (MMP) i n t o t h e s urround i ng ti ssue t o b r eak d ow n t h e e x tracell u lar matri x t o all o w t h e E Cs t o mi gr at e and o r gan i ze t he msel v es i n t o ho ll o w t ub es t h at e v e n t u all y e volve i n t o a m a t u r e ne t wo r k o f b l ood v essels . Pr o a ng i og e n ic fact o rs o r po siti ve r e gu lat o r s o f ang i ogenes i s i n cl ud e v asc u lar e ndo t h elial g r o wt h fact o r (VEG F ), bas i c fi b r ob l as t g r ow t h fact o r (PlGF) , p latelet- d eri v e d g r o wt h f act or ( P DG F) , p l acen t a l g r ow t h fact o r , tra n sf o rmi ng g r o wt h fact o r -β , p lei o t roph i ns, and o t he r s . Ac ti v ati on o f t h e hypox ia-i ndu ci b le fact o r 1 (HIF-1) v i a t u m o r - assoc i a t ed hypox ic c ond iti on s is als o i nvo l v e d i n t h e upr e gu l a ti on o f seve r a l ang i og e n ic fact o rs . T h e a ng i og e n ic switc h als o i nvo l v es t he down r egu l a ti on o f a ng i og e n esis s upp ress o r p r o tei n s , w h ic h i n cl ud e endos t a ti n, ang i os t a ti n, t h r o m bo s pond i n, a nd o t h ers . , M o st no ta b l y , howeve r , i s t he li nk b etwee n ma ny on c og e n es a nd a ng i og e n esis a nd t h e si gn ifi can t r o l e oncogen es p la y i n d ri v i ng t h e a ng i og e n ic switc h . | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,154 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Angiogenic Switch and Regulatory P r oteins | nan nan | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.1 | 0.095 | 0.1 | 5 |
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20,155 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Angiogenic Switch and Regulatory P r oteins | nan nan | Th ese p r oang i ogen i c oncoge nes no t on l y i ndu ce t h e e xp ressi on o f stim u lat o r s, bu t m ay a l so do w n re gu late i nh i b it o rs o f a ng i og e n esis . | 6 | 0.09 | 0.085 | 0.07 | 0.065 | 0.045 | 0.03 | 0.09 | 1 |
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20,156 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Endogenous Inhibitors of Angiogenesis | null | nan nan | Th e i nfrequency o f mi c r oscop ic i n sit u t u m o rs t h at act u all y und e r go t h e a ng i og e n i c sw it ch ( <1 %) sugg ests t h at n at u rall y o cc u rri ng e ndog e nou s | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,157 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Endogenous Inhibitors of Angiogenesis | null | nan nan | i nh i b it ors ex i s t i n t he body t o d efe nd a g ai n st t h e a ng i og e n ic switc h i n p at ho l og i c cond iti ons and t o l i mit phy si o l og ic a ng i og e n esis . T h ese ci r c u lati ng endogenous i nh i b it o rs c ou l d als o p re v e n t micr o sc op ic metasta ses fr o m g r ow i ng i n t o v isi b le t u m o rs . Earl y st ud ies by La ng er et al de m ons tr a t ed t he poss i b le e x iste n ce o f s u c h i nh i b it o rs t h r ough t h e e x t r acti on o f a f unc ti ona l i nh ibit o r fr o m cartila g e , a tiss u e t h at is poo rl y v asc u la r i zed. Si nce t hen, doz e n s o f e ndog e nou s a ng i og e n esis i nh i b it o rs h a v e b e en i den tifi ed, so m e o f w h ic h are liste d i n Ma ny of t h e e ndogenous i nh i b it o r s o f a ng i og e n esis t h at h a v e b ee n d isc ov ere d t o date a r e pro t eo l y ti ca ll y c l eaved fra g me n ts o f lar g er p r o tei n s t h at are mem b er s o f eit h e r t he c l o tti ng / coagu l a ti o n s y stem o r mem b ers o f t h e e x tracell u lar mat r i x fa mil y o f g l ycop r o t e i n s . E ndo stati n is t h e m o st well-st ud ie d e ndog e nous ang i ogenes i s i nh i b it o r Ot h er po te n t e ndog e nou s a ng i og e nes i s i nh i b it o r s i nc l ud e t h r o m bo s pond i n - 1 a nd t u mstati n T h e d isc ov e ry o f vasoh i b i n, an en d og e nou s i nh i b it o r t h at is selecti v el y i ndu ce d i n E Cs by p r oang i ogen i c s tim u lat o r y g r o wt h fact o rs s u c h as VEG F , d em on st ra t ed t he ex i s t ence o f a n i n tri n sic a nd EC-s p ecific fee db ac k i nh i b it or con tr o l m echan i s m w h ereas m o st e ndog e nou s i nh i b it o rs o f a ng i og e nes i s a r e ex tri ns i c t o E Cs . M o re rece n tl y , a sec ond e ndo t h eli u m- produ ce d nega ti ve r egu l a t o r o f a ng i og e n esis h as b ee n d isc ov ere d, t h e Dl l4 - No tc h sig na li ng sys t e m , B ot h i n tri n sic fact o rs h a v e si n ce b ee n s ho w n to c on t ro l t u m o r ang i ogenes i s b y a n a u t o re gu lat o r y o r n e g ati v e-fee db ac k mec h a n ism . T he D ll 4 - No t ch ax is h as emer g e d as a critical re gu lat o r o f t u m or a ng i ogenes i s, and i nh i b it o rs o f t h is p at h wa y (e .g., d emciz u ma b, t he a n ti -D ll4 m onoc l ona l an ti body ) are c u rre n tl y b ei ng i nv esti g ate d i n earl y ph ase t r i a l s o f so li d t u m o r s | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,158 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Endogenous Inhibitors of Angiogenesis | null | nan nan | Pe rhaps t he m os t co m pe lli ng g e n etic e v i d e n ce t h at e ndog e nou s i nh i b it ors supp r ess pa t ho l og ic a ng i og e n esis was ob ser v e d i n st ud ies u si ng mice d e f i c i en t i n t u m s t a ti n, endo stati n, o r t h r o m bo s pond i n 1 (TSP- 1 ) . | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,159 | UND E RS T ANDING TH E ANGIOGENIC PROC E SS | Endogenous Inhibitors of Angiogenesis | nan nan | Th ese e xpe rim en t s de m ons tr a te t h at no rmal phy si o l og ic le v els o f t h e i nh i b it ors can r e t a r d t he t u m or g r o wt h a nd t h at t h eir a b se n ce lea d s t o e nh a n ce d ang i ogenes i s and i n crease d t u m o r g r o wt h by tw o - t o t h reef o l d, st rong l y sugges ti ng t ha t endog e nou s i nh i b it o rs o f a ng i og e n esis ca n act a s e ndo t h e l i u m- spec ifi c t u m o r supp ress o rs . T h e c onn ecti on b etwee n a t u m o r s uppr es so r p r o t e i n and ang i o ge n esis is b est ill u strate d by t h e classic t u m o r s uppr es so r p53. p53 i nh i b it s ang i og e n esis by i n creasi ng t h e e xp ressi on o f TSP-1 by r ep r ess i ng V E G F a nd b asic fi b r ob last g r o wt h fact o r –b i nd i ng pro tei n and by deg r ad i ng H IF- 1 , w h ic h b l o c k s t h e do w n stream i ndu cti on o f V E G F exp r ess i on. New e v i d e n ce s ugg ests t h at p53 als o i nd i r ectl y down r egu l a t es V EGF e xp ressi on v ia t h e reti nob last o ma p at hway i n a p21 - dependen t m anne r du ri ng s u stai n e d hypox ia . F u rt h erm o re , p53 -me d iated i nh i b iti on o f ang i og e n esis ma y als o o cc u r i n p art v ia t h e | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
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20,160 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | null | null | nan nan | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,161 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | null | null | nan nan | Th e f i r s t ang i ogenes i s i nh i b itor was re po rte d i n 1980 a nd i nvo l v e d t h e l ow - do se a d mi n i s tr a ti on o f i n t e rf e r on α (IFN- α ) . O v er t h e n e x t d eca d e , se v e r al co m pounds we r e d i scov ere d t o h a v e po te n t a n tia ng i og e n ic acti v i t y , i n cl ud i ng p r o t a mi ne and p l a t e let fact o r 4 , tra hyd r o c o rtis o l , a nd t h e fu ma g ill in ana l og T N P- 470 . T h e p r oo f o f c on ce p t t h at ta r g eti ng a ng i og e nes i s i s an e f f ec ti ve s trate gy f o r treati ng ca n cer came wit h t h e a pprov a l o f t he fir s t ang i ogen esis i nh i b it o r , b e v aciz u ma b, by t h e U . S . F ood a nd Drug Ad mi n i s tr a ti on (F D A) . Si n ce t h e n, se v eral a n tia ng i og e n ic a g e nts h a v e r ec e i ved F DA app r ova l f o r ca n cer treatme n t ( , a nd t h ree a dd iti ona l agen t s ( pegap t an i b, ra n i b iz u ma b, a nd afli b erce p t) are a pp r ov e d for t h e t rea tm en t o f we t age -relate d mac u lar d e g e n erati on. | 6 | 0.005 | 0.02 | 0.03 | 0.01 | 0.02 | 0.005 | 0.03 | 3 |
20,162 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Rationale for Antiangiogenic Therapy | null | nan nan | Rationale for Antiangiogenic Therapy | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,163 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Rationale for Antiangiogenic Therapy | null | nan nan | An tia ng i ogen i c t he r apy s t e m s fr o m t h e f und ame n tal c on ce p t t h at t u m o r grow t h, i nvas i on, and m e t as t a sis are a ng i og e n esis d e p e nd e n t; t hu s , b l o c king | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,164 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Rationale for Antiangiogenic Therapy | null | nan nan | b l ood vesse l r ec r u itm en t t o s t a r v e p rimar y a nd metastatic t u m o rs is a r ati on al app r oach. T he mi c r ov asc u lar EC recr u ite d by a t u m o r h as b ec ome a n im po rt an t second t a r ge t i n ca n cer t h era p y . U n li k e t h e ca n cer cell (t h e pr ima ry t a r ge t o f cy t o t ox i c ch em o t h era py ) , w h ic h is g e n eticall y un sta b l e w it h unp r ed i c t ab l e m u t a ti ons, t h e g e n etic sta b ilit y o f ECs ma y ma k e t h e m less s u s cep ti b l e t o acqu ir ed d r ug resista n ce M o re ov e r , ECs i n t h e mic rov a scu l a r bed o f a t u m o r ma y s uppo rt 50 t o 100 t u m o r cells . C oup li ng t h is am p lifi ca ti on po t en ti a l t og et h er wit h t h e l o wer t ox icit y o f m o st a ng i og e nes i s i nh i b it o r s r esu lts i n t h e u se o f a n tia ng i og e n ic t h era p y , w h i ch s hou l d b e s i gn ifi can tl y l ess t ox ic t h a n c onv e n ti on al c h em o t h era p y . How e v e r , t he va ri ab l e r espon ses o f a n tia ng i og e n ic t h era py ob ser v e d i n d i f f e r e n t t u m o r t ypes and t he f act t h at a ng i og e n esis i nh i b it o rs h a v e no t d eli v e r ed t he bene fit s i n iti a ll y e nv isa g e d s ugg est t h at t h e p recise mec h a n ism o f ac ti on o f ang i og e n esis i nh i b it o rs is c o m p le x a nd remai n s i n c o m p l e t e l y unde r s t ood. | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
20,165 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Modes of Action of Antiangiogenic Agents | null | nan nan | Modes of Action of Antiangiogenic Agents | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,166 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Modes of Action of Antiangiogenic Agents | null | nan nan | a ng i og e nes i s i nh i b it o r s such as celec ox i b, a c y cl ooxyg e n ase- 2 (COX- 2 ) i nh i b it o r , wh i ch i nh i b it s ang i og e n esis by i n creasi ng le v els o f e ndo stati n . S o m e d r ugs possess an ti ang i og e n ic p r op erties bu t wit h mec h a n isms t hat a r e no t co m p l e t e l y unde r s t ood, s u c h as t h ali do mi d e a nd its a n al og s , le n ali dom i de and po m a li do m id e , referre d t o as imm uno m odu lat o r y d r ugs. Th ali do mi de was o ri g i na ll y s h o w n t o i nh i b it a ng i og e n esis by D’Amat o et al i n 1994 and t h i s was subs e qu e n tl y c on firme d i n se v eral d iffere n t i n v it ro a nd ex v i vo assays . I n teresti ng l y , un li k e o t h er mec h a n isms o f acti on, t he an ti ang i ogen i c ac ti v it y o f t h ali do mi d e is b elie v e d t o re qu ire e n z y mat ic ac ti va ti on. T he ex t en t t o w h ic h t h e a n tia ng i og e n ic p r op erties o f t h ali do mi de and it s ana l ogs p la y a r o le i n its a n tim y el o ma acti v it y is no t clea r l y u nde r s t ood. S eve r a l m e c h a n isms h a v e b ee n p r opo se d t h at i nvo l ve t h e down r egu l a ti on o f cy t ok i n es i n EC , t h e i nh i b iti on o f EC p r o liferati on, t h e d ec r e ase i n t he l eve l o f c irc u lati ng ECs , o r t h e m odu lati on o f a dh esi on m o lec u l es be t ween t he m u lti p le m y el o ma cells a nd t h e e ndog e nou s bone ma rrow str o m a l ce ll s, t he r eby d ecreasi ng t h e p r odu cti on o f VEGF a nd i n te r le uk i n 6 (IL- 6 ) T he i m m uno m odu lat o r y a g e n ts are d isc u sse d i n gr eate r de t a il i n ano t he r sec ti on o f t h is te x t book. E x am p les o f t h e v ari ous t yp es of ang i ogenes i s i nh i b it o rs are h i gh li gh te d i n | 6 | 0.05 | 0.075 | 0.08 | 0.03 | 0.06 | 0.09 | 0.09 | 6 |
20,167 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Modes of Action of Antiangiogenic Agents | null | nan nan | Drug s w it h an ti ang i ogen i c acti v it y ma y b e classifie d as eit h er d irect o r i nd i r ect ang i ogenes i s i nh i b it o rs . A d irect a ng i og e n esis i nh i b it o r b l o c k s v asc u la r E Cs fr o m p r o lif e r a ti ng, mi g rati ng, o r i n creasi ng t h eir s u r v i v al i n r es pon s e t o p r oang i ogen i c p r o tei n s . T h e y ta r g et t h e acti v ate d e ndo t h eli um d i r ectl y and i nh i b it m u lti p l e ang i og e n ic p r o tei n s . E x am p les o f d irect a ng i og e nes i s i nh i b it o r s i nc l ud e ma ny o f t h e e ndog e nou s i nh i b it o rs o f a ng i og e nes i s, such as endos t a ti n, a ng i o stati n, a nd TSP- 1. I nd irect a ng i og e nes i s i nh i b it o r s dec r ea se o r b l o c k e xp ressi on o f a t u m o r cell produ ct , neu tr a li ze t he t u m o r p r odu ct itself , o r b l o c k its rece p t o r on ECs . Th e lim i t a ti on t o i nd ir ec t i nh i b it o rs is t h at , ov er time , t u m o r cells ma y ac qu i r e mu t a ti ons t ha t l ead t o i n crease d e xp ressi on o f o t h er p r o a ng i og e nic | 6 | 0.05 | 0.075 | 0.08 | 0.09 | 0.06 | 0.04 | 0.09 | 4 |
20,168 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Modes of Action of Antiangiogenic Agents | null | nan nan | pro tei n s t ha t a r e no t b l ocked by t h e i nd irect i nh i b it o r . T h is ma y g i v e t h e a pp ea r a nce o f d r ug r es i s t ance a nd warra n ts t h e a dd iti on o f a sec ond a n tia ng i ogen i c agen t , one t ha t w ou l d tar g et t h e e xp ressi on o f t h ese upr e gu l a t ed p r oang i ogen i c p rotei n s . E x am p les o f d r ug s t h at i n terfere wi th t h e a ng i ogenes i s - s i gna li ng pa t h wa y i n cl ud e t h e a n ti-VEGF m ono cl on al a n ti bod i es and s m a ll-m o l ecu l e t y r o si n e –k i n ase i nh i b it o rs . T h ese d r ug s ta r g et t he m a j o r s i gna li ng pa t h wa y s i n t u m o r a ng i og e n esis: VEG F , PDG F , a nd t h eir r espec ti ve r ecep t o r s , as well as o t h er g r o wt h fact o rs a nd / o r si gn ali ng pa t hways. VEG F ( a l so known as vas c u lar p ermea b ilit y fact o r) is a po te n t pro a ng i ogen i c g r ow t h f ac t o r a nd its e xp ressi on is up re gu late d by m o st ca n ce r c e ll t ypes. It s tim u l a t es EC p r o liferati on, mi g rati on, a nd s u r v i v al a s w ell as i nduces i nc r eased vascu lar p ermea b ilit y . T h e d i f fere n t f o rms o f VEG F b i nd t o tr ans m e m b r an e rece p t o r t y r o si n e k i n ases ( R TK) on ECs: VEG FR 1 (Flt- 1 ) , V E G F R2 (KDR/Fl k - 1 o r k i n ase i n sert do mai n r ece p t or /f e t a l li ve r k i nase 1 ) , or VEGFR 3 (Flt- 4 ) . T h is res u lts i n rece p t o r d ime r iz a ti on, ac ti va ti on, and au t opho s pho r y lati on o f t h e t y r o si n e –k i n ase do mai n, t he r eby tri gge ri ng do w n stream si gn ali ng p at h wa y s . Ot h er si gn al ing m o lec u l es t ha t m ay r ep r esen t attracti v e t h era p e u tic ta r g ets i n cl ud e PDG F a nd t h e a ng i opo i e ti ns ( Ang1, A ng2 ) . PDGF-B/PDGF rece p t o r (R)-β p la ys a n im po rt an t r o l e i n t he r ec r u itme n t o f p eric y tes a nd mat u rati on o f t h e mic rov a scu l a t u r e Ang2, wh ic h b i nd s t h e T ie- 2 rece p t o r , is m o stl y e xpr ess ed i n t u m o r -i nduced n e ov asc u lat u re , w h ere by its selecti v e i nh i b i tion r es u lts i n r educed E C p r o lif e r a ti on . T h e a ng i opo ieti n s are als o i nvo l v e d in l y m ph a ng i ogenes i s, t he f o rmati on o f n ew l y m ph atic v essels , w h ic h p la ys a k e y ro le i n t u m o r m e t as t as i s. An i n crease d A ng2 /A ng1 rati o c o rrelates with t u m or a ng i ogenes i s and poo r pr ogno sis i n ma ny ca n cers , t hu s ma k i ng t he a ng i opo i e ti ns an a ttr ac ti ve t h era p e u tic tar g et . A ng i opo ieti n i nh i b it o rs ar e c urr e n tly unde r i nves ti ga ti on i n t h e p recli n ical a nd cli n ical setti ng. O t h er s tr a t eg i es f o r t a r ge ti ng a ng i og e n esis i nvo l v e t h e t u m o r mic ro e nv ir on m en t . B r eakdown o f t h e e x tracell u lar matri x is re qu ire d t o all ow ECs t o mi g r a t e i n t o su r round i ng tiss u es a nd p r o liferate i n t o n ew b l ood vesse l s ; t hus, d r ugs t ha t ta r g et MMPs , e n z y mes t h at catal y ze t h e | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,169 | DRUG DEVE LOP MENT OF ANGIOGEN E SIS IN H IBI T ORS | Modes of Action of Antiangiogenic Agents | null | nan nan | br ea kdown o f t he m a tri x, can als o i nh i b it a ng i og e n esis . H o we v e r , cli n ic al d e v el opmen t o f MM P i nh i b itors (MMPI) h as y iel d e d d isa ppo i n ti ng r es u lts . In te g ri ns a r e ce ll su rf ace adh esi on m o lec u les t h at p la y a n esse n tial r ole i n cell –ce ll and ce ll – m a tri x adh esi on as well as i n tra n smitti ng si gn als im por ta n t f o r ce ll mi g r a ti on, in v asi on, p r o liferati on, a nd s u r v i v al . T h e i nvo l v em en t o f i n t eg ri n i n t u m o r a ng i og e n esis was d em on strate d i n st udies t h at s ho w t he β- 4 subun it o f i n te g ri n p r o m o ti ng e ndo t h elial mi g rati on a nd i nv asi on Agen t s t ha t t a r ge t i n te g ri n s (i nh i b it o rs o f α v β 3 a nd α v β 5 ) h a v e b ee n e va l ua t ed as po t en ti a l t h era p e u tic op ti on s a nd i n cl ud e etaraciz u mab , cile ng iti de, and i n t e t u m u m ab. H o we v e r , all t h ree i n te g ri n i nh i b it o rs h a ve prov e n t o be l a r ge l y i ne f f ec ti v e i n v ari ou s earl y a nd late sta g e ca n cer t r ials . I n su mm a r y , t he do w n stream e f fects o f a n tia ng i og e n ic a g e n ts , in a dd iti on t o b l ock i ng ang i oge nesis , ma y i nvo l v e i ndu ci ng v essel re g ressi on, pro m o tin g sens iti za ti on t o r ad i o t h era py a nd c h em o t h era py by d e p ri v i ng E Cs of V E G F ’ s p r osu r v i va l sign als , a nd i nh i b iti ng t h e recr u itme n t o f pro a ng i ogen i c bone m a rr ow–d eri v e d cells as well as re du ci ng t h e self- r e n e w al capab ilit y o f cance r s tem cells . | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
20,170 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | null | null | nan nan | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | 6 | 0.05 | 0.08 | 0.09 | 0.1 | 0.07 | 0.06 | 0.1 | 4 |
20,171 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | null | null | nan nan | Th e fo ll ow i ng sec ti on r ev i ew s t h e c u rre n t FDA-a pp r ov e d a ng i og e n esis i nh i b it ors ( ) . T hese a g e n ts i n cl ud e: ( 1 ) t h e m ono cl on al a n ti- VEG F a n ti bod i es ( bevac i zu m ab a nd zi v -afli b erce p t); ( 2 ) small-m o lec u l e t yro si n e –k i nase i nh i b it o r s (TKI) (s o rafe n i b, s un iti n i b, p az op a n i b, v a nd etani b, ax iti n i b, cabozant i n i b, a nd re go rafe n i b ); a nd ( 3 ) t h e mamma lian ta r g et of r apa m yc i n (m T OR ) i nh i b it o rs (temsir o lim u s a nd e v er o lim u s) , as e x am p les o f d r ugs t ha t posse ss a n tia ng i og e n ic acti v it y . Ot h er a pp r ov e d drug s t ha t a l so i nh i b it ang i og e n esis as a sec ond ar y f un cti on, s u c h as | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
20,172 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | null | null | nan nan | t h ali do mi de, a r e d i scussed i n g reater d etail i n a no t h er secti on o f t h is te x t book and a r e p r esen t ed i n . | 6 | 0.05 | 0.01 | 0.02 | 0.01 | 0.01 | 0.01 | 0.05 | 1 |
20,173 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | null | nan nan | Anti-VEGF Therapy | 6 | 0.05 | 0.075 | 0.1 | 0.09 | 0.08 | 0.06 | 0.1 | 3 |
20,174 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | Bevacizumab | nan nan | Bevacizumab | 6 | 0.05 | 0.07 | 0.08 | 0.06 | 0.04 | 0.09 | 0.09 | 6 |
20,175 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | Bevacizumab | nan nan | Be v aciz u m ab i s a r eco m b i nan t hu ma n ize d a n ti – VEGF-A m ono cl on al a n ti body t ha t r ece i ved F DA app r ov al i n Fe b r u ar y 2004 f o r u se i n c o m b i na ti on t he r apy w it h fl uo r ou racil- b ase d re g ime n s f o r metastatic c o l or ectal cance r . Bevac i zu ma b b i nd s VEGF a nd p re v e n ts t h e i n teracti on o f VEG F to it s r ecep t o r s (Flt- 1 and KDR) on t h e s u rface o f ECs . It is t h e fi rst a n tia ng i ogen i c agen t c li n i ca ll y p r ov e n t o e x te nd s u r v i v al f o ll o wi ng a la r ge, r a ndo mi zed, doub l e - b li nd, ph ase III st udy i n w h ic h b e v aciz u ma b was a d mi n is te r ed i n co m b i na ti on wit h bo l u s iri no teca n, 5 -fl uo r ou racil , a nd le u c ovo ri n (IFL) as fir s t-li ne th era py f o r metastatic c o l o rectal ca n cer ( CRC ). I n 2006, it s app r ova l e x te nd e d t o first- o r sec ond -li n e treatme nt o f p atie n ts wit h m e t as t a ti c ca r c i no ma o f t h e c o l on o r rect u m . T h is r ec o mm enda ti on i s based on t h e d em on strati on o f a statisticall y si gn ific ant im prov e men t i n ove r a ll su r v i v al (OS) i n p atie n ts recei v i ng b e v aciz u ma b p l u s FOL F OX4 ( 5 -fl ou r ou r aci l , le u c ovo ri n, a nd ox ali p lati n ) w h e n c o m p a red t o t hose r ece i v i ng FOLFOX 4 al on e . I n Ja nu ar y 2013, it was fur t h e r app r oved t o tr ea t m C RC f o r sec ond -li n e treatme n t w h e n u se d wi th f l uoropy rimi d i ne - based ( co m b i n e d wit h iri no teca n o r ox ali p lati n ) c h em o t he r apy a ft e r d i sease prog ressi on f o ll o wi ng a first-li n e treatme n t with a b e v aci zu m ab - con t a i n i ng r eg ime n b ase d on cli n ical b e n efits ob ser v e d i n t h e r a ndo mi zed phase III s t udy (ML 18147 ) . Des p ite t h e b e n efit i n t h e metastati c se tti ng, t he add iti on o f b e v aciz u ma b d i d no t im p r ov e cli n ical ou tc o m es i n t he ad j uvan t se tti ng i n CRC . I n 2006, b e v aciz u ma b rece ived a n a dd iti ona l app r ova l f o r use i n c o m b i n ati on wit h car bop lati n a nd p aclita x el , and i s i nd i ca t ed f o r first-li n e treatme n t o f p atie n ts wit h unr esect ab l e, l oca ll y advanced, rec u rre n t , o r metastatic non s qu am ou s , non– small - cell l ung cance r ( N S C LC) b ase d on t h e d em on strati on o f a | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
20,176 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | Bevacizumab | nan nan | c ondu cte d i n pa ti en t s w it h p r ev i ou sl y un treate d, metastatic clear cell RCC . Me d ia n PFS was 8.4 m on t hs v ers u s 4.9 m on t h s i n fa vo r o f t h e b e v aciz u m ab a r m . Bot h s t ud i es d i d no t de m on strate a statisticall y si gn ifica n t a dv a n t age i n O S . Cli n i ca l s t ud i es o f bevac i zu ma b i n c o m b i n ati on wit h ox ali p lati n -c on tai n i ng and 5 -fl uo r ou r ac il –b ase d re g ime n s h a v e s ho w n t h at c o m b i n a tion t h e r a py i s we ll t o l e r a t ed w it h t ox icit y no t b ei ng s ub sta n tiall y g reater t h a n t h at of t he che m o t he r apy a l on e Si d e e f fects i n cl ud e d g ra d e 3 hyp e r te ns i on, g r ade 1 o r 2 p r o tei nu ria , a sli gh t i n crease (less t h a n tw o p e r ce n ta ge po i n t s ) i n g r ade 3 o r 4 b lee d i ng, a nd im p aire d s u r g ical w ound h eali ng i n pa ti en t s who unde rwe n t s u r g er y du ri ng treatme n t wit h b e v aciz u m ab. Howeve r , po t en tiall y life-t h reate n i ng e v e n ts (e .g., arterial and v e nou s t h r o m boe m bo li c even ts , g astr o i n testi n al p erf o rati on, h em op t y sis, r is k of ova ri an f a il u r e ) have oc c u rre d i n s o me p atie n ts , t hu s re qu iri ng cl ose p atie n t m on it o ri ng i n i nd i v i du als w ho are at g reater ris k o f a dv erse e v e nts . | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
20,177 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | nan nan | 6 | 0.05 | 0.07 | 0.08 | 0.09 | 0.1 | 0.1 | 0.1 | 5 |
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20,178 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | nan nan | In a r ec en t m e t a - ana l ys i s o f RC T s , b e v aciz u ma b i n c o m b i n ati on wit h c h em o t he r apy o r b i o l og i c t her a p y , c o m p are d wit h c h em o t h era py al on e , was ass o ciate d w it h i nc r eased tr eat me n t-relate d m o rtalit y . A lt hough f ou r phase III r a n do mize d st ud ies h a v e d em on strate d im prov e men t s i n PFS f o r ova ria n ca n cer (OC) — tw o first-li n e trials (GO G 218 a nd I CON7 ) and t wo i n rec u rre n t OC [ p l a ti nu m- r esist an t (AURELI A T r ial ) or p l a ti num - sens iti ve (OCEANS T rial)] — t h e r o le o f b e v aciz u ma b in O C r emai ns con tr ove r s i a l . Be vaciz u ma b is a pp r ov e d f o r u se i n c o m b i n at ion w it h c he m o t he r apy i n t he fir s t- a nd sec ond -li n e treatme n t o f a dv a n ce d O C i n Europe, bu t it i s no t cu rr en tl y lice n se d i n t h e U n ite d States f o r t h is i nd icati on. Ma t u r e O S da t a and p re d icti v e b i o mar k ers are k e y t o d efi n i ng t h e s ub s e t s o f pa ti en t s who wi ll m o st li k e b e n efit fr o m t h is t h era p y . M o r e r ece n tl y , a r ando mi zed, phase III trial (GOG 240 ) h as d em on strate d f o r t he f i r st tim e t ha t bevac i zu m ab c a n p r o l ong OS a nd PFS f o r w o me n wit h a dv a n ce d, r ecu rr en t , o r pe r s i st e n t cer v ical ca n cer t h at was no t c u ra b le w ith sta nd a rd che m o t he r ap y . A t t h e time o f writi ng, t h ere are c u rre n tl y ov er 400 acti v el y r ec r u iti ng, ongo i ng tr i als i nv esti g ati ng t h e cli n ical b e n efits o f b e v aciz u m ab i n co m b i na ti on w it h c h em o t h era p e u tic re g ime n s o r as | 6 | 0.005 | 0.09 | 0.03 | 0.06 | 0.01 | 0.08 | 0.09 | 2 |
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20,179 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | nan nan | a d j uv a nt t he r apy i n va ri ous s t ag es a nd t yp es o f ca n cer ) . | 6 | 0.09 | 0.085 | 0.07 | 0.065 | 0.1 | 0.095 | 0.1 | 5 |
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20,180 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | Ziv-aflibercept | nan nan | Ziv-aflibercept | 6 | 0.05 | 0.07 | 0.08 | 0.09 | 0.1 | 0.1 | 0.1 | 5 |
20,181 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | Anti-VEGF Therapy | Ziv-aflibercept | nan nan | Z i v- a f li be r cep t ( p r ev i ous l y kno w n as afli b erce p t o r VEGF T ra p ) is a r ec o m b i nan t hu m an i zed f us i on p r o tei n o f t h e e x tracell u lar do mai n s o f VEG F recep t o r 1 ( V E G F R1 ) a nd VEGFR 2 wit h t h e c on sta n t re g i on (Fc) o f hu ma n imm unog l obu li n (I g )G 1 t h at b i nd s t o VEGF-A , VEGF-B , PlGF 1, a nd Pl G F 2, t he r eby p r even ti ng t h ese li g a nd s fr o m b i nd i ng t o a nd acti v ati ng t h ei r c ogna t e r ecep t o r s . Zi v -afli b erce p t h as a h i gh er VEGF-A b i nd i ng a f f i n it y a nd m o r e po t en t b l oc ka d e o f VEGFR 1 o r VEGFR 2 acti v ati on t han b e v aciz u m ab I n t u m o r m od els , zi v -afli b erce p t e x erts its a n tia ng i og e n i c e f f ects thr ough r eg r ess i ng t u m o r v asc u lat u re a nd size , rem od eli ng o r nor mali z i ng su r v i v i ng vascu lat u re , a nd i nh i b iti ng ascites f o rmati on . I n Augu st 2012, z i v - a fli be r cep t recei v e d re gu lat o r y a pp r ov al f o r u se i n c o m b i na ti on w it h 5 -fl uo r ou r ac il , le u c ovo ri n, a nd iri no teca n (FOLFIRI) f o r t h e t r eatm en t o f pa ti en t s w it h metastatic CRC t h at is resista n t t o o r t h at has progr esse d f o ll ow i ng tr ea tm en t wit h a n ox ali p lati n -c on tai n i ng re g ime n. Res u lts f r o m t he p i vo t a l phas e III VELOUR trial s ho we d t h at zi v -a f li b e r c ep t p l us F O LFI R I s t a tisticall y a nd si gn ifica n tl y im p r ov e d PFS ( me d ia n PFS , 6.90 ve r sus 4.6 7 m on t h s , res p ecti v el y ) , OS (me d ia n OS , 13.50 ve r sus 12.06 m on t hs, r e s p ecti v el y ) , a nd ov erall res pon se rates ( 19% v e r s u s 1 1.1 % , r espec ti ve l y ) r e lati v e t o p lace bo p l u s FOLFIRI . T ox icitie s r elate d t o z i v - a fli be r cep t we re c on siste n t wit h t ho se e xp ecte d fr o m t h e a nti - VEG F d r ug c l ass. T he fr equen c y o f v asc u la r -relate d a dv erse e v e n ts a pp ea r e d t o be h i ghe r w it h z i v -afli b erce p t t h a n b e v aciz u ma b treatme n t wh e n c ompa r ed ac r oss tri a l s. C u rre n t cli n ical d ata are i n s u f ficie n t t o d i r ectl y co m pa r e z i v - a fli be r c e p t a nd b e v aciz u ma b i n t h e first- o r sec ond -li n e setti ng f o r m e t as t a ti c CR C . | 6 | 0.08 | 0.09 | 0.07 | 0.08 | 0.09 | 0.08 | 0.09 | 2 |
20,182 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Sorafenib | nan nan | S or a f e n ib i s a s m a ll-m o l ecu l e Raf k i n ase a nd VEGF rece p t o r k i n ase (VEG F R2 and V E G F R3 ) i nhib it o r . It h as b ee n s ho w n t o e xh i b it b r o a d -s p ect ru m e f f ec t s on m u lti p l e ta r g ets (PDGF rece p t o r (PDGFR) , stem cel l f act or ( c -K IT) r ecep t o r , p38 ) t h at a f fect t h e mai n te n a n ce o f t h e t u m o r v asc u lat u r e and ang i ogenes i s . I n Decem b er 2005, t h e FDA g ra n te d a pprov a l f o r so r a f en i b, wh i ch is c on si d ere d t h e first m u lti k i n ase i nh i b it o r , for t h e t rea tm en t o f pa ti en t s wit h a dv a n ce d RCC . Safet y a nd e f ficac y o f s or a f e n i b was p r oven i n t he la r g est ra ndo mize d ph ase III st udy c ondu cte d in a dv a n ce d RCC t ha t showed pro l ong PFS i n fa vo r o f s o rafe n i b . I n Nov em be r 2007, so r a f en i b w as a pp r ov e d f o r t h e treatme n t o f p atie n ts w ith unr esect ab l e hepa t oce ll u l a r c arci no ma (HCC) b ase d on t h e st udy res u lts in p atie n ts wit h advanced HCC w ho h a d no t recei v e d p re v i ou s s y stemic t r eatme n t . Med i an su r v i va l and t h e time t o ra d i o l og ic p r og ressi on were n ea r l y 3 m on t hs l onge r f o r pat ie n ts treate d wit h s o rafe n i b t h a n f o r t ho se g i v e n p l acebo I n Nove m ber 2013, s o rafe n i b recei v e d a n ew i nd icati on und e r t he F D A ’ s p ri o rit y r ev iew p r og ram f o r t h e treatme n t o f l o call y r ec urr e n t o r m e t as t a ti c, p r og ressi v e d iffere n tiate d t hy r o i d carci no ma (D T C) r e fr act ory t o r ad i oac ti ve i od i n e (RAI) treatme n t b ase d on po siti v e res u lts fro m t he phase III D E C ISI ON trial . T reatme n t wit h s o rafe n i b im p r ov e d PF S ( t he p rim a r y endpo i n t o f t h e trial) by 41 % c o m p are d wit h p lace bo (10.8 v er sus 5.8 m on t hs, r esp ecti v el y ; h azar d rati o [HR] , 0.587, 95 % c onf i d e nce i n t e r va l [ C I] [ 0.454 t o 0.758 ]; p <0.0001 ) . T h e ov erall r es pon s e r a t es we r e 12 % f o r p atie n ts w ho recei v e d s o rafe n i b v ers u s 1 % f o r t h e p lace bo a rm . A lt hough only a bou t 5 % t o 15 % o f t hy r o i d ca n cer p ati ents b ec o me re fr ac t o r y t o RA I , no sta nd ar d treatme n ts are a v aila b le a nd, t hus, s or a f e n i b i s t he fir s t agen t spe cificall y a pp r ov e d f o r RAI-resista n t DTC . S or a f e n ib was gene r a ll y we ll t o lerate d wit h a p re d icta b le safet y p r o file . C o mm on adve r se even t s i nc l ud e d iarr h ea , ras h / d es qu amati on, fati gu e , h a nd–foo t sk i n r eac ti on, a l ope cia , a nd n a u sea/ vo miti ng. Gra d e 3 / 4 a dv er se e v e n ts we r e 38 % f o r so r a f en i b v ers u s 28 % f o r p lace bo. S o rafe n i b -i ndu c ed hyp e r te ns i on occu rr ed i n pa ti en ts wit h metastatic RCC . T h e treatme n t- r elate d hype rt ens i on was no t ed t o b e a class effect ob ser v e d no t on l y wit h VEG FR i nh i b it o r s, bu t a l so wit h t h e VEGF m ono cl on al a n ti body as wel l . | 6 | 0.06 | 0.07 | 0.08 | 0.09 | 0.1 | 0.1 | 0.1 | 5 |
20,183 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Sunitinib | nan nan | Sunitinib | 6 | 0.085 | 0.092 | 0.076 | 0.081 | 0.083 | 0.084 | 0.092 | 2 |
20,184 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Sunitinib | nan nan | ast h e n ia , sk i n abno rm a liti es, and altere d taste , were m o re c o mm on i n p atie n ts rece i v i ng sun iti n i b. In a dd iti on, a d ecrease i n left v e n tric u lar ejecti on fr ac ti on and seve r e hyp erte n si on were als o m o re c o mm on l y r e por te d i n t he sun iti n i b a rm . Gra d e 3 o r 4 treatme n t-emer g e n t a dv erse e v e n ts we r e r epo rt ed i n 56 % vers u s 51 % o f p atie n ts on s un iti n i b v ers u s p lace bo, r espec ti ve l y . | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
20,185 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Pazopanib | nan nan | Paz op a n i b i s a second - gene r at i on, m u ltitar g ete d TKI t h at b i nd s t o VEG F R- 1, -2, -3 , P DG F R - α and -β , c -KI T , a nd se v eral o t h er k e y p r o tei n s r es pon sibl e f o r ang i ogenes i s, tu m o r g r o wt h, a nd cell s u r v i v al . Paz op a n i b e xh i b ite d i n v i vo and i n v itr o a cti v it y a g ai n st t u m o r g r o wt h, a nd earl y cli n ical t ri a l s de m ons tr a t ed p ote n t a n tit u m o r a nd a n tia ng i og e n ic acti v it y | 6 | 0.05 | 0.09 | 0.08 | 0.07 | 0.06 | 0.08 | 0.09 | 2 |
20,186 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | nan nan | A ph ase III c li n i ca l tri a l i n tr e atme n t- n aï v e a nd c y t ok i n e- p retreate d p atie nts w it h a dvanced and / o r m e t as t at ic RCC s ho we d a si gn ifica n t im p r ov eme nt in PF S a nd t u m o r r esponse co m p are d wit h p lace bo , lea d i ng t o t h e a pp r oval of p az opan i b i n t he Un it ed States i n Oct ob er 2009. A rece n t , ra ndo mize d ph ase III tri a l ( COM P AR Z) co m p are d t h e e f ficac y a nd safet y o f p az op a nib a nd s un i t i n i b as fir s t-li ne t he ra py i nvo l v i ng p atie n ts wit h metastatic RCC a nd d e mons tr a t ed t ha t bo t h p az op a n i b a nd s un iti n i b h a v e similar e f ficac y , bu t t h e saf e t y and qua lit y - o f-l i fe p r o files fa vo r p az op a n i b . I n A p ril 2012, p az op a n i b was app r oved f o r t h e treatme n t o f p atie n ts wit h metastatic non a d i pocy ti c so ft ti ssue sa r co ma w ho h a v e recei v e d p ri o r c h em o t h era py fo ll ow i ng a phase III tri a l t hat d em on strate d a statisticall y si gn ifica n t im prov e men t i n PFS . T he m ed ia n PFS was 4.6 m on t h s f o r p atie n ts r ecei v i ng pazopan i b ve r sus 1.6 m on t h s f o r t h e p lace bo arm . T h e d r ug is g e n e r ally we ll t o l e r a t ed, w it h t h e m o st c o mm on a dv erse e v e n ts b ei ng d ia rrh ea , f a ti gue, ano r ex i a, hyp erte n si on, a nd h air d e p i g me n tati on, as w ell as la bora t o r y abno rm a liti es i n ele v ate d as p artate ami no tra n sferase a nd ala n i n e a mi no tr ans f e r ase. P azop a n i b h as s ho w n cli n ical acti v it y i n a v ari ety of t u m o r s, i nc l ud i ng b r eas t can ce r , t hy r o i d ca n ce r , HCC , a nd cer v ical | 6 | 0.05 | 0.075 | 0.08 | 0.03 | 0.09 | 0.09 | 0.09 | 5 |
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20,187 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | nan nan | ca n ce r . Ongo i ng phase II and III trials are f u rt h er e v al u ati ng p az op a n i b in t h ese m a li gnanc i es. | 6 | 0.05 | 0.07 | 0.08 | 0.09 | 0.1 | 0.06 | 0.1 | 5 |
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20,188 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | V andetanib | nan nan | V a nd etani b i s an o r a l , s m a ll-m o lec u le TKI t h at i nh i b its t h e acti v it y o f R ET k i n ase , V E G F R, ep i de rm a l g r o wt h fact o r rece p t o r (EGFR) , p r o tei n t y r o s ine k i n ase 6 ( BRK ) , TIE 2, m e m b ers o f t h e e ph ri n (EPH) rece p t o rs k i n ase f amil y , and m e m be r s o f t he Src famil y o f t y r o si n e k i n ases . V a nd eta n i b r e du ce d endo t he li a l ce ll mi g rati on, p r o liferati on, s u r v i v al , a nd a ng i og e n e sis i n v it ro, and it dec r eased t u m o r v essel p ermea b ilit y a nd i nh i b ite d t u m o r grow t h and m e t as t as i s i n v i vo. I n A p ril 20 1 1, v a nd eta n i b recei v e d U . S . r e gu lat o r y app r ova l f o r t he treatme n t o f s y m p t o matic o r p r og ressi v e me du llar y t hy r o i d cance r ( M TC) i n p atie n ts wit h un resecta b le , l o call y a dv a n ce d, o r m e t as t a ti c d i sea se . U n til t h e a pp r ov al o f v a nd eta n i b, no s y stemi c t he r apy was app r ov e d f o r t h e treatme n t o f un resecta b le MTC , ma k i ng it t he fir s t m o l ecu l a rl y tar g ete d a g e n t a pp r ov e d f o r t h is d isease . Res u lts of a r ando mi zed phase III trial o f p atie n ts wit h un resecta b le , l o c ally a dv a n ce d, o r m e t as t a ti c M T C d em on strate d statisticall y si gn ifica n t a nd cli n ically m ean i ng f u l im p r ov eme n ts i n PFS f o r v a nd eta n i b c o m p are d wit h p lace bo (HR, 0.46 ; 95 % C I , 0.31 t o 0.69 ; p <0.001 ) . C o mm on g ra d e 3 a nd 4 t ox i c iti es ( >5 %) we r e d iarr h ea a nd / o r c o litis , hyp erte n si on a nd hyp e r te ns i ve c ri s i s, f a ti gue, hypo calcemia , ras h, a nd c o rrecte d QT i n ter val (Q T c ) p r o l onga ti on. G i ven t he t ox icit y p r o file , w h ic h i n cl ud es Q T c pro l onga ti on and sudden dea t h, v a nd eta n i b is on l y a v aila b le t h r ough a r est r icte d d i s tri bu ti on p r og r am. V a nd eta n i b is als o t h e first ta r g ete d d r ug to s how e v i dence o f e f fi cacy i n a ra ndo mize d ph ase II trial i n p atie n ts wit h l o call y advanced o r m e t as t a tic d iffere n tiate d t hy r o i d carci no ma , a nd a ph ase III tri a l i s cu rr en tl y unde rwa y . Earl y ph ase st ud ies are als o b ei ng c ondu cte d i n so li d t u m o r s, i nc l ud i ng GIST a nd k i dn e y a nd p a n creatic ca n ce r s . | 6 | 0.08 | 0.07 | 0.09 | 0.08 | 0.09 | 0.08 | 0.09 | 3 |
20,189 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Axitinib | nan nan | Ax iti n i b i s a po t en t and se l ec ti v e sec ond - g e n erati on i nh i b it o r o f VEGFR- 1, -2, a nd -3. T he i n v itr o ha lf-ma x imal i nh i b it o r y c on ce n trati on (IC 50 ) o f a x iti n i b i s 10 -f o l d l owe r f o r the VEGF famil y o f rece p t o rs t h a n f o r o t h er TKI s s uch as pazopan i b, sun i t i n i b, o r s o rafe n i b I n Ja nu ar y 2012, a x iti nib r ecei v e d app r ova l f o r t he tr ea tme n t o f a dv a n ce d RCC after t h e fail u re o f on e pr i o r sys t e mi c t he r apy ba se d on a ph ase III trial (AXIS) c o m p ari ng the e f f icac y and sa f e t y o f ax iti n i b v ers u s s o rafe n i b as a sec ond -li n e treatme nt for metast a ti c RCC . T he m e d ia n PFS was 6.7 m on t h s wit h a x iti n i b c o m p a red t o 4.7 m on t hs w it h s o rafe n i b (HR , 0.67 ; 95 % CI , 0.54, 0.81 ; one -si d e d p < 0.0001 ) . T h i s im p r ov eme n t i n PFS was g reater i n t h e c y t ok i n e- pr et r eat ed subg r oup i n co m pa ris on wit h t h e s un iti n i b - p retreate d s ubg r oup. Th e m o st fr equen t adve r se ev e n ts wit h a x iti n i b were d iarr h ea (all g ra d e), hyp e r te ns i on ( a ll g r ade ) , f a ti gu e , d ecrease d a pp etite , n a u sea , a nd dy s phonia. M or e ove r , hype rt ens i on, nause a , dy s phon ia , a nd hypo t hy r o i d ism were m o r e c o mm on w it h ax iti n i b, whe r ea s p almar –p la n tar er y t h r ody sest h esia , al op ecia , and r ash we r e m o r e fre qu e n t wit h s o rafe n i b. A ph ase III trial (AGILE) co m pa ri ng ax iti n i b w it h s o rafe n i b as first-li n e t h era py i n p atie nts w it h t r e a tm en t- na ï ve m e t as t a t i c RCC d em on strate d no si gn ifica n t d i f fer ence i n me d i an PFS be t ween pa ti e nts treate d wit h a x iti n i b o r s o rafe n i b . | 6 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 1 |
20,190 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | nan nan | Add iti ona ll y , ax iti n i b i s be i ng st ud ie d as a si ng le a g e n t as well as i n c o m b i na ti on w it h che m o t he r apy acr o ss se v eral t u m o r t yp es i n cl ud i ng HCC , N SC L C , and panc r ea ti c and t hy r o i d ca n cers . | 6 | 0.09 | 0.085 | 0.075 | 0.065 | 0.055 | 0.045 | 0.09 | 1 |
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20,191 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Cabozantinib | nan nan | Cabozantinib | 6 | 0.085 | 0.092 | 0.076 | 0.043 | 0.061 | 0.085 | 0.092 | 2 |
20,192 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Cabozantinib | nan nan | Ca bo za n ti n i b ( X L 184 ) i s a sm all-m o lec u le TKI wit h po te n t acti v it y t o w a r d t h e M E T r ecep t o r and V E G FR 2, as well as a nu m b er o f o t h er rece p t o r t yro si n e k i nases, i nc l ud i ng R E T , KI T , AXL , a nd F LT - 3. MET is t h e on ly known r e cep t o r f o r hepa t ocy t e g r o wt h fact o r (HGF) , a nd its si gn ali ng acti v it y p l ays a key r o l e i n t u m o ri g e n ic g r o wt h, metastasis , a nd t h era p e u t ic r esista nce. T he dys r egu l a t ed e xp ressi on a nd / o r acti v ati on o f MET a nd H GF h a v e b e en im p li ca t ed i n t he dev el op me n t o f nu mer ou s hu ma n ca n cers i n cl ud i ng g li o m a ; m e l ano m a ; a nd h e p at o cell u la r , re n al , g astric , p a n creat ic, | 6 | 0.09 | 0.075 | 0.06 | 0.05 | 0.08 | 0.09 | 0.09 | 1 |
20,193 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Cabozantinib | nan nan | pro state, ova ri an, b r eas t , and lung ca n cers , a nd is o fte n c o rrelate d wit h poo r progno si s Recen t s t ud i es h a v e d etermi n e d t h at t h e MET p at h wa y p la ys a n im po rt an t r o l e i n t he deve lo p me n t o f resista n ce t o VEGF p at h wa y i nh i b iti o n and t ha t t he use o f VEGFR i nh i b it o rs , s u c h as s un iti n i b, s or a f e n i b, o r a V E G F R2 -t a r g eti ng a n ti bod y , ca n res u lt i n t h e d e v el op me nt of a n a gg r ess i ve t u m o r pheno t yp e c h aracterize d by i n crease d i nv asi v e n e ss a nd met as t as i s . T hus, t h ere is a n a dv a n ta g e t o ta r g eti ng bo t h t h e M ET a nd VEG F pa t hways t o d i s r u pt a ng i og e n esis , t u m o ri g e n esis , a nd ca n cer progr ess ion. I n Nove m be r 2012, ca bo za n ti n i b recei v e d U . S . re gu lat o r y a pprov a l f o r p r og r ess i ve m e tastatic MTC b ase d on t h e ph ase III trial t h a t d em on st ra t ed a s t a ti s ti ca ll y s i gn ifica n t PFS p r o l ong ati on f o r t h e ca bo za n ti n i b -tr ea tm en t a rm . T h e estimate d me d ia n PFS was 1 1.2 m onths for ca bozan ti n i b ve r sus 4.0 m on t h s f o r p lace bo (HR , 0.28 ; 95 % CI , 0.19 to 0.40 ; p <0.001 ) . Manageab l e t ox icities i n cl ud e d d iarr h ea , p almar –p la n tar e ry t hrodyses t hes i a, dec r eased wei gh t a nd a pp etite , n a u sea , a nd fati gu e . Ca bo za n ti n i b has been e f f ec ti v e a g ai n st se v eral s o li d ca n cers , i n cl ud i ng M T C , b r eas t , N S C L C, m e l ano ma , a nd li v er ca n ce r , a nd is c u rre n tl y b ei ng st ud ie d in c li n i ca l tri a l s i n a nu m b er o f t u m o r t yp es , wit h t h e m o st si gn i f ic an t r esu lt s obse r ved i n t h e re du cti on o f bon e metastatic lesi on s in cast r ati on -r es i s t an t p r os t a t e c a n ce r | 6 | 0.07 | 0.06 | 0.03 | 0.02 | 0.01 | 0.005 | 0.07 | 1 |
20,194 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Regorafenib | nan nan | Regorafenib | 6 | 0.1 | 0.095 | 0.08 | 0.075 | 0.06 | 0.045 | 0.1 | 1 |
20,195 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Regorafenib | nan nan | Re gor a fen i b i s a s m a ll-m o l ecu le TKI o f m u lti p le mem b ra n e- bound a nd i n t r acell u l a r k i nases i nc l ud i ng RE T , VEGFR 1, VEGFR 2, VEGFR 3, KI T , P DG FR- α, P DG F R -β , F G F R 1 , FGFR 2, TIE 2, DDR 2, T r k A , E ph2 A , R AF - 1, BR A F , BRA F V600 E , S A PK 2, PTK 5, a nd A b l p at h wa y s . Re go rafe nib is st ru ct u r a ll y r e l a t ed t o so r a fe n i b a nd d iffers fr o m t h e latter by t h e p res ence of a f l uor i ne a t o m i n t he cen t e r ph e ny l ri ng, res u lti ng i n h i gh er i nh i b it o r y po te n c y aga i ns t va ri ous p r oang i og e n ic rece p t o rs t h a n s o rafe n i b, i n cl ud in g VEG FR 2 and F G F R1. I n S ept em b er 2012, re go rafe n i b was a pp r ov e d f or t h e t r eatm en t o f pa ti en t s w it h mCRC w ho h a v e b ee n p re v i ou sl y treate d with f l uoropy rimi d i ne - , oxa li p l a ti n-, a nd iri no teca n - b ase d c h em o t h era p y , wit h an | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
20,196 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | T y r osine–Kinase Inhibitor Therapy | Regorafenib | nan nan | a n ti -VEG F t he r ap y , and if K RAS wil d t yp e , wit h a n a n ti-EGFR t h era p y . Th e ph a se III CORR E C T tri a l t h at res u lte d i n a pp r ov al o f t h e d r ug d em on st ra t ed a m ed i an O S o f 6.4 m on t h s i n t h e re go rafe n i b g r oup v ers us 5.0 m on t hs i n t he p l acebo g r oup (HR , 0.77 ; 95 % CI , 0.64 t o 0.94 ; on e-si ded p = 0.0052 ) . Rego r a f en i b i s t h e first TKI wit h s u r v i v al b e n efits i n mCRC t h at h as p r og r essed a ft e r a ll s ta nd ar d t h era p ies . I n Fe b r u ar y 2013, it r ecei v e d ano t he r i nd i ca ti on f o r t h e treatme n t o f p atie n ts wit h l o call y a dv a n ce d, un r esec t ab l e, o r metastatic GIST w ho h a v e b ee n p re v i ou sl y t r eate d w it h im a ti n i b and sun iti n i b. T h is was b ase d on po siti v e fi nd i ng s o f t h e ph as e III GR I D tri a l t ha t d em on strate d a me d ia n PFS o f 4.8 m on t h s f o r r e gor a f e n i b and 0.9 m on t hs f o r p lace bo (HR , 0.27, 95 % CI , 0.19 t o 0.39; p < 0.0001). I n bo t h s t ud i es, re go rafe n i b p r ov i d e d si gn ifica n t im p r ov em ents i n PF S to h i gh l y r e fr ac t o r y pat ie n t popu lati on s w ho h a v e p r og resse d on sta nd a rd tr ea tm en t s. T he m os t c o mm on a dv erse e v e n ts t h at were g ra d e 3 o r h i gh e r a nd r e l a t ed t o r ego r a f en i b were h a nd– f oo t s k i n reacti on, fati gu e , d ia rrh ea , hype rt ens i on, and r ash o r d es qu amati on. Its cli n ical d e v el op me nt as a si n gl e agen t o r i n co m b i na ti on wit h sta nd ar d c h em o t h era p e u tic a g en ts i n v a r i ous m a li gnan t t u m o r s is ongo i ng a nd i n cl ud es a ph ase III trial i n p atie n ts wit h HCC whose d i s ease h as p r og resse d after treatme n t wit h s or a f e n i b. | 6 | 0.09 | 0.08 | 0.07 | 0.06 | 0.05 | 0.04 | 0.09 | 1 |
20,197 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | m T OR Inhibitors | null | nan nan | Th e m T OR pa t hway i s a cen tral c o m pon e n t o f t h e PI 3 K/A k t si gn ali ng p at hw a y and a r egu l a t o r o f ma ny b i o l og ic p r o cesses t h at are esse n tial f or a ng i og e nes i s, ce ll p r o lif e r a ti on, a nd meta bo lism . I nh i b iti on o f t h e m T O R k i n ase p r even t s downs tr ea m si gn ali ng v ia t h e A k t p at h wa y , res u lti ng i n i nh i b iti o n o f p r o t e i n tr ans l a tio n a nd cell g r o wt h. mTOR p la y s a k e y r o le in a ng i og e nes i s and spec ifi ca ll y re gu lates t h e e xp ressi on o f HIF- 1, w h ic h is upr e gu l a t ed by t he l oss o f t he von Hi pp el – Li nd a u g e n e i n RCC . I n Ma y 2007, tem s ir o lim us was app r ov e d f o r t h e treatme n t o f a dv a n ce d RCC . E f f icac y and sa f e t y we r e de mo n strate d i n a ph ase III st udy i n p re v i ou sl y un t r eated pa ti en t s ( n = 626 ) wit h poo r ris k feat u res o f metastatic RCC | 6 | 0.005 | 0.09 | 0.08 | 0.04 | 0.01 | 0.01 | 0.09 | 2 |
20,198 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | m T OR Inhibitors | null | nan nan | assi gn ed t o one o f t h r ee tr ea t m e n t arms: IFN- α al on e , temsir o lim u s 25 mg al on e , or t he co m b i na ti on o f t e msir o lim u s ( 15 m g ) a nd IFN- α . Si ng le-a g e n t te ms ir o lim us was associ ate d wit h a statisticall y si gn ifica n t im prov e men t i n O S when co m p are d wit h IFN; t h e a dd iti on o f temsir o li mus t o IFN did no t im p r ove O S . T h e res u lts o f t h e ph ase III INTORSECT tria l c o m p a red t he e f fi cacy o f t e m s ir o lim u s a nd s o rafe n i b i n t h e sec ond -li n e t r eatme n t o f m e t as t a ti c RCC after d isease p r og ressi on on s un iti n i b d em on st ra t ed t ha t t e m s ir o lim u s d i d no t im p r ov e s u r v i v al ov er s o rafe n i b in t h e sec ond -li ne se tti ng . T he si gn ifica n t OS d i f fere n ce i n fa vo r o f s or a f e n i b ( s tr a tifi ed HR, 1.31 ; 95 % CI , 1.05 t o 1.63 ; tw o -si d e d p = 0.01 ) s ugg est ed t ha t V E G F R i nh i b iti on ma y b e a b etter op ti on t h a n m T OR i nh i b it ors f o r pa ti en t s p r og r es si ng on s un iti n i b. T h e m o st c o mm on a dv er se r eacti ons t ha t occu rr ed we r e r a s h, ast h e n ia , m u c o sitis , n a u sea , e d ema , a nd a nor e x i a. Ra r e, bu t se ri ous adv erse reacti on s ass o ciate d wit h temsir o lim us i n cl ud e d i n t e r s titi a l l ung d i se ase , bo wel p erf o rati on, a nd ac u te re n al fail u r e. Ev e ro lim us ( RAD001 ) wa s a pp r ov e d i n Marc h 2009 f o r p atie n ts wit h a dv a n ce d RCC whose d i sease h a d p r og resse d on VEGFR-tar g ete d t h era py ( s un iti n i b o r so r a f en i b ) . E f fi ca c y was d em on strate d i n a ph ase 3 trial t h a t st udy m e t it s p rim a r y endpo i n t wit h a me d ia n PFS o f 4.9 a nd 1.9 m on t hs in t h e e v e r olim us and p l acebo a rms , res p ecti v el y (HR , 0.33 ; p <0.0001 ) | 6 | 0.08 | 0.07 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 1 |
20,199 | CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y | m T OR Inhibitors | nan nan | 6 | 0.05 | 0.08 | 0.09 | 0.1 | 0.07 | 0.06 | 0.1 | 4 |