Patent Abstract:
the invention features a method for the treatment or prevention of mucositis in an individual undergoing or preparing to undergo cancer treatment . the method includes administering a therapeutically effective amount of an inhibitor of nf - κb to an individual undergoing or preparing to undergo a treatment for cancer . in certain embodiments , the inhibitor is a compound having the formula : where r 1 and r 4 are oh , and r 2 and r 3 are independently oh or h , provided that when r 1 and r 2 are both oh , r 1 and r 2 cannot be disposed ortho to one another , and when r 3 and r 4 are both oh , r 3 and r 4 cannot be disposed ortho to one another . the compounds of formula i may be cis or trans .

Detailed Description:
resveratrol ( trans - 3 , 4 ′, 5 - trihydroxystilbene ) can be used therapeutically to attenuate mucositis , as disclosed in u . s . application ser . no . 60 / 313 , 081 , hereby incorporated by reference . resveratrol is a polyphenolic phytoalexin that is found in grapes , fruits , and root extracts of the weed polygonum cuspidatum . resveratrol is isolated from grapes predominantly in the trans form . it is a non - flavinoid polyphenol that demonstrates a number of biologic activities including being anti - inflammatory , an anti - oxidant , modulating cell growth , and being anticarcinogenic ( stojanovic et al . arch biochem biophy 2001 , 391 : 79 - 89 ). by suppressing the induction of phosphorylation and nuclear translocation of p65 subunit by tumor necrosis factor - alpha ( tnf - α ), resveratrol blocked the activation of nf - κb ( manna et al . j . immunol . 2000 , 164 : 6509 - 19 ). since activation of nf - κb by radiation therapy or chemotherapy in cancer patients leads to mucositis , compounds that inhibit the activation or action of nf - κb may be effective in treating or preventing mucositis . accordingly , the invention features a method for the treatment or prevention of mucositis . this method is based on the administration of a therapeutically effective amount of an inhibitor of nf - κb to a patient undergoing or about to undergo radiation or chemotherapy treatments for cancer . since resveratol has shown efficacy in treating mucositis , other hydroxystilbenes , e . g ., the compounds of formula i , may show similar or greater efficacy . additional compounds that are known to inhibit nf - κb include , without limitation , α - lipoic acid ( sen et al ., 1998 ; suzuki et al ., 1992 ), α - tocopherol ( islam et al ., 1998 ), anetholdithiolthione ( adt ) ( sen et al ., 1996 ), butylated hydroxyanisole ( bha ) ( israel et al ., 1992 ; schulze - osthoff et al ., 1993 ), cepharanthine ( okamoto et al ., 1994 ), caffeic acid phenethyl ester ( 3 , 4 - dihydroxycinnamic acid , cape ) ( natarajan et al ., 1996 ), catechol derivatives ( suzuki et al ., 1994 ), diethyldithiocarbamate ( ddc ) ( schreck et al ., 1992b ), deferoxamine ( sappey et al ., 1995 ), dihydrolipoic acid ( suzuki et al ., 1995 ), disulfiram ( schreck et al ., 1992b ), dimethyldithiocarbamates ( dmdtc ) ( pyatt et al ., 1998a ), curcumin ( diferulolylmethane ) ( singh and aggarwal , 1995b ), ebselen ( schreck et al ., 1992b ), epc - k1 ( phosphodiester compound of vitamin e and vitamin c ) ( hirano et al ., 1998 ) epigallocatechin - 3 - gallate ( egcg ; green tea polyphenols ) ( lin et al ., 1997 ; yang et al ., 1998 ), ethylene glycol tetraacetic acid ( egta ) ( janssen et al ., 1999 ), gamma - glutamylcysteine synthetase ( gamma - gcs ) ( manna et al ., 1999 ), glutathione ( cho et al ., 1998 ; schreck et al ., 1992b ), l - cysteine ( mihm et al ., 1991 ) lacidipine ( cominacini et al ., 1998 ), manganese superoxide dismutase ( mn - sod ) ( manna et al ., 1998 ), melatonin ( gilad et al ., 1998 ; mohan et al ., 1995 ), n - acetyl - l - cysteine ( nac ) ( schreck et al ., 1991 ), nordihydroguaiaritic acid ( ndga ) ( brennan et al ., 1998 ; israël et al ., 1992 ; schulze - osthoff et al ., 1993 ; staal et al ., 1993 ), orthophenanthroline ( schreck et al ., 1992b ), phenylarsine oxide ( pao , tyrosine phosphatase inhibitor ) ( arbault et al ., 1997 ), pyrrolidinedithiocarbamate ( pdtc ) ( schreck et al ., 1992a ), quercetin ( musonda and chipman , 1998 ), rotenone ( schulze - osthoff et al ., 1993 ), s - allyl - cysteine ( sac , garlic compound ) ( geng et al ., 1997 ), tepoxalin ( 5 -( 4 - chlorophenyl )- n - hydroxy -( 4 - methoxyphenyl ) - n - methyl - 1h - pyrazole - 3 - propanamide ) ( kazmi et al ., 1995 ), vitamin c ( staal et al ., 1993 ), vitamin e derivatives ( suzuki and packer , 1993a ), α - torphryl succinate ( staal et al ., 1993 ; suzuki and packer , 1993b ), α - torphryl acetate ( suzuki et al ., 1993a ), pmc ( 2 , 2 , 5 , 7 , 8 - pentamethyl - 6 - hydroxychromane ) ( suzuki et al ., 1993a ), peptide aldehydes : allnl ( n - acetyl - leucinyl - leucinyl - norleucinal , mg101 ), llm ( n - acetyl - leucinyl - leucinyl - methional ), z - llnv ( carbobenzoxyl - leucinyl - leucinyl - norvalinal , mg1 15 ), z - lll ( carbobenzoxyl - leucinyl - leucinyl - leucinal , mg132 ) ( palombella et al ., 1994 ; grisham et al ., 1999 ; jobin et al ., 1998a ), lactacystin , β - lactone ( fenteany et al ., 1998 ; grisham et al ., 1999 ), boronic acid peptide ( grisham et al ., 1999 ; iqbal et al ., 1995 ), ubiquitin ligase inhibitors ( yaaron et al ., 1997 ), cyclosporin a ( frantz et al ., 1994 ; marienfield et al ., 1997 ; mccaffrey et al . 1994 ; meyer et al ., 1997 ; wechsler et al ., 1994 ), fk506 ( tacrolimus ) ( okamoto et al ., 1994 ; venkataraman et al ., 1995 ), deoxyspergualin ( tepper et al ., 1995 ), apne ( n - acetyl - dl - phenylalanine - β - naphthylester ) ( higuchi et al ., 1995 ), btee ( n - benzoyl l - tyrosine - ethylester ) ( rossi et al ., 1998 ), dcic ( 3 , 4 - dichloroisocoumarin ), dfp ( diisopropyl fluorophosphate ), tpck ( n - 60 - tosyl - l - phenylalanine chloromethyl ketone ), tlck ( n - α - tosyl - l - lysine chloromethyl ketone ) ( d ′ acquisto et al ., 1998 ), aspirin , sodium salicylate ( frantz and o &# 39 ; neill , 1995 ; kopp and ghosh , 1994 ; yin et al ., 1998 ), bay - 117821 ( e3 (( 4 - methylphenyl )- sulfonyl )- 2 - propenenitrile ), bay - 117083 ( e3 (( 4 - t - butylphenyl )- sulfonyl )- 2 - propenenitrile ), cycloepoxydon , 1 - hydroxy - 2 - hydroxymethyl - 3 - pent - 1 - enylbenzene ( gehrt et al ., 1998 ), extensively oxidized low density lipoprotein ( ox - ldl ), 4 - hydroxynonenal ( hne ) ( brand et al ., 1997 ; page et al ., 1999 ), ibuprofen ( palayoor et al ., 1999 ), nitric oxide ( no ) ( katsuyama et al ., 1998 ; matthews et al ., 1996 ), prostaglandin a1 ( rossi et al ., 2000 ), sanguinarine ( pseudochelerythrine , 13 - methyl -[ 1 , 3 ]- benzodioxolo -[ 5 , 6 - c ]- 1 , 3 - dioxolo - 4 , 5 phenanthridinium ) ( chaturvedi et al ., 1997 ), sulfasalazine ( wahl et al ., 1998 ), sulindac ( yamamato et al ., 1999 ), yopj ( encoded by yersinia pseudotuberculosis ) ( schesser et al ., 1998 ), α - melanocyte - stimulating hormone ( α - msh ) ( manna and aggarwal , 1998a ), β - lapachone ( manna et al ., 1999a ), capsaicin ( 8 - methyl - n - vanillyl - 6 - nonenamide ) ( singh et al ., 1996b ), core protein of hepatitis c virus ( hcv ) ( shrivastava et al ., 1998 ), diamide ( tyrosine phosphatase inhibitor ) ( toledano and leonard , 1991 ; singh and aggarwal , 1995a ), emodin ( 3 - methyl - 1 , 6 , 8 - trihydroxyanthraquinone ) ( kumar et al ., 1998 ), erbstatin ( tyrosine kinase inhibitor ) ( natarajan et al ., 1998 ), estrogen ( e2 ) ( sun et al ., 1998 ), fungal gliotoxin ( pahl et al ., 1996 ), genistein ( tyrosine kinase inhibitor ) ( natarajan et al ., 1998 ), il - 13 ( manna and aggarwal , 1998b ), leflunomide metabolite ( a77 1726 ) ( manna and aggarwal , 1999 ), pervanadate ( tyrosine phosphatase inhibitor ) ( singh and aggarwal , 1995a ; singh et al ., 1996a ), phenylarsine oxide ( pao , tyrosine phosphatase inhibitor ) ( mahboubi et al ., 1998 , singh and aggarwal , 1995a ), resiniferatoxin ( singh et al ., 1996 ), sesquiterpene lactones ( parthenoide ) ( hehner et al ., 1998 ), β - amyloid protein ( bales et al ., 1998 ), glucocorticoids ( dexametasone , prednisone , methylprednisolone ) ( auphan et al ., 1995 ; brostjan et al ., 1996 ; ray and prefontaine , 1994 ; scheinman et al ., 1995 ), il - 10 ( ehrlich et al ., 1998 ; lentsch et al ., 1997 ), il - 11 ( trepicchio and dorner , 1998 ), leptomycin b ( lmb ) ( rodriguez et al ., 1999 ), nls cell permeable peptides ( lin et al ., 1995 ), o , o ′- bismyristoyl thiamine disulfide ( bmt ) ( shoji et al ., 1998 ), adp ribosylation inhibitors ( nicotinamide , 3 - aminobenzamide ) ( le page et al ., 1998 ), atrial natriuretic peptide ( anp ) ( gerbes et al ., 1998 ), atrovastat ( hmg - coa reductase inhibitor ) ( bustos et al ., 1998 ; hemandez - presa et al ., 1998 ), calcitriol ( 1a , 25 - dihydroxyvitamine d3 ) ( harant et al ., 1998 ), clarithromycin ( miyanohara et al ., 2000 ), diamide ( toledano and leonard , 1991 ), e3330 ( quinone derivative ) ( hiramoto et al ., 1998 ), glycyrrhizin ( wang et al ., 1998 ), herbimycin a ( iwasaki et al ., 1992 ; mahon and o &# 39 ; neill , 1995 ), hypericin ( bork et al ., 1999 ), hydroquinone ( hq ) ( pyatt et al ., 1998b ), il - 4 ( manna and aggarwal 1999 ), iκb - like proteins ( encoded by asfv ) ( powell et al ., 1996 ; revilla et al ., 1998 ), kt - 90 ( morphine synthetic derivative ) ( sueoka et al ., 1998 ), metals ( chromium , cadmium , gold , mercury , zinc , arsenic ) ( shumilla et al ., 1998 ; yang et al ., 1995 ), mevinolin , 5 ′- methylthioadenosine ( mta ) ( law et al ., 1992 ), n - ethyl - maleimide ( nem ) ( toledano and leonard , 1991 ), nicotine ( sugano et al ., 1998 ), pentoxifylline ( 1 -( 5 ′- oxohexyl ) 3 , 7 - dimetylxanthine , ptx ) ( biswas et al ., 1993 ; wang et al ., 1997 ), phenyl - n - tert - butylnitrone ( pbn ) ( kotake et al ., 1998 ), pituitary adenylate cyclase - activating polypeptide ( pacap ) ( delgado et al ., 1998 ), pyrithione ( kim et al ., 1999 ), quinadril ( ace inhibitor ) ( bustos et al ., 1998 ; hernandez - presa et al ., 1998 ), ribavirin ( fiedler et al ., 1996 ), secretory leukocyte protease inhibitor ( slpi ) ( jin et al ., 1997 ), serotonin derivatives ( n -( p - coumaroyl ) serotonin , sc ) ( kawashima et al ., 1998 ), silymarin ( saliou et al ., 1998 ), vascular endothelial growth factor ( vegf ) ( oyama et al ., 1998 ; gabrilovich et al ., 1998 ), vasoactive intestinal peptide ( vip ) ( delgado et al ., 1998 ), d609 ( phosphatidylcholine - phospholipase c inhibitor ) ( bergmann et al ., 1998 ), ro31 - 8220 ( pkc inhibitor ) ( bergmann et al ., 1998 ), sb203580 ( p38 mapk inhibitor ) ( bergmann et al ., 1998 ), triptolide ( pg490 , extract of chinese herb ) ( qiu et al ., 1999 ), ly294 , 002 ( sizemore et al ., 1999 ), mesalamine ( egan et al ., 1999 ), wortmannin ( fungal metabolite ) ( manna and aggarwal , 2000 ), lactacystin , idoxifene , raloxifene , droloxifene , tiremifene , and tamoxifen . further examples of compounds that inhibit nf - κb are disclosed in narayanan et al . ( u . s . pat . no . 5 , 591 , 840 ), bennett et al . ( u . s . pat . no . 6 , 069 , 008 ), lai et al . ( u . s . pat . no . 6 , 316 , 502 ), morishita et al . ( u . s . pat . no . 6 , 262 , 033 ), qabar et al . ( u . s . pat . no . 6 , 117 , 896 ), and lino et al . ( u . s . pub . no . 2001 / 018441 ), each of which is hereby incorporated by reference . flavinoids , e . g ., those found in soybean ( such as genestein ), can also be used to attenuate mucositis according to the invention . among other possible flavinoids that can be used in the invention are galloyl flavonol glycosides such as quercetin or kaempferol . topical application is preferred , but compounds can be administered using any standard means for administering therapeutic compounds , including , without limitation , oral , sublingual , intravenous , and intraperitoneal injection . dosages and timing of administration can be determined using routine methods for such determination , e . g . a therapeutically effective amount is administered one , two , or three times a day . the compounds may be administered , for example , at any time before , during , or after radiation or chemotherapy . treatment may be continued as long as necessary . hamster models of chemotherapy - induced mucositis and radiation - induced mucositis have been developed . in the latter model , specific doses of acute radiation were targeted to the designated mucosa , with protection of other areas by a customized lead shield . the reproducibility of the model has been validated , with the consistent appearance of ulcerative mucositis between days 15 and 18 following radiation . using this model , the efficacies of various topical agents have been tested for their abilities to modify the course of radiation - induced mucositis . this study analyzed resveratrol in both topical and intraperitoneal dosing at concentrations of 1 mm and 5 mm . the control group was dosed topically with water . an acute radiation dose of 40 gy on day 0 was administered in order to produce severe mucositis around day 15 . the use of acute radiation to induce mucositis was preferable to the use of either fractionated radiation or chemotherapy for these initial studies . the acute model had little systemic toxicity , resulting in fewer animal deaths . this fact permitted the use of smaller groups in the initial studies . the acute model has been used successfully to demonstrate the presence or absence of efficacy for a large number of compounds . the acute radiation model is therefore appropriate as an initial protocol for screening diverse families of compounds . the grade of mucositis was scored , starting from day 6 following irradiation ( which occurs on day 0 ), and for every second day thereafter , through and including day 20 . the effect on mucositis of each drug treatment compared to placebo was assessed according to the following parameters : the difference in the number of days hamsters in each group have severe ( score ≧ 3 ) mucositis . on each evaluation day , the number of animals with a blinded mucositis score of & gt ; 2 in each drug treatment group , was compared to the control group . differences were analyzed on a daily as well as a cumulative basis . successful treatment was considered a statistically significant lower number of hamsters with a score ≧ 3 in a drug treatment group , versus control as determined by chi - square analysis . the rank sum differences in daily mucositis scores . for each day of evaluation , the scores of the control group were compared to those of the treated group using the non - parametric rank sum analysis . treatment success was considered as a statistically significant lowering of scores in the treated group on 2 or more days from day 8 to day 20 . male golden syrian hamsters ( charles river laboratories , wilmington , mass . or harlan sprague dawley , indianapolis , ind . ), aged 5 to 6 weeks , with body weight approximately 90 g at project commencement , were used . animals were individually numbered using an ear punch and housed in small groups of approximately 6 animals per cage . animals were acclimatized for at least one week prior to project commencement . during this period , the animals were observed daily in order to reject animals that presented poor condition . this study used forty ( 40 ) hamsters that were randomly divided into five groups of eight animals per group . each group was assigned a different treatment as follows : group 1 animals 1 - 8 topical , tid water group 2 animals 9 - 16 intraperitoneal , qd 1 mm resveratrol group 3 animals 17 - 24 intraperitoneal , qd 5 mm resveratrol group 4 animals 25 - 32 topical , tid 1 mm resveratrol group 5 animals 33 - 40 topical , tid 5 mm resveratrol mucositis was induced using an acute radiation protocol . a single dose of radiation ( 40 gy / dose ) was administered to all animals on day 0 . radiation was generated with a 250 kilovolt potential ( 15 ma ) source at a focal distance of 50 cm , hardened with a 0 . 35 mm cu filtration system . irradiation targeted the left buccal pouch mucosa at a rate of 121 . 5 cgy / minute . prior to irradiation , animals were anesthetized with an intraperitoneal injection of sodium pentobarbital ( 80 mg / kg ). the left buccal pouch was everted , fixed , and isolated using a lead shield . the test compounds were kept frozen and protected from light when not in use during the entire study . each day of dosing , an aliquot of test compound was removed from the plastic bottles using a sterile syringe , and 0 . 2 ml of the compound was injected into each animal in groups 2 and 3 . intraperitoneal ( ip ) dosing was performed once per day from day − 1 to day 20 . topical dosing was performed 3 times per day for animals in groups 1 , 4 and 5 . a needleless tuberculin syringe , containing 0 . 2 ml of the test compound or water , was inserted into the left cheek pouch and the drug deposited into the pouch . all hamsters were weighed daily and their survival recorded , in order to assess possible differences in animal weight among treatment groups as an indication for mucositis severity and / or possible toxicity resulting from the treatments . starting on day 6 of each study and then every second day thereafter ( days 8 , 10 , 12 , 14 , 16 , 18 , and 20 ), animals were photographed and evaluated for mucositis . parameters to be measured include the mucositis score , weight change , and survival . for the evaluation of mucositis , the animals were anesthetized with inhalation anesthetics , and the left pouch everted . mucositis was scored visually by comparison to a validated photographic scale , ranging from 0 for normal , to 5 for severe ulceration ( clinical scoring ). in descriptive terms , this scale was defined as follows : score : description : 0 pouch completely healthy . no erythema or vasodilation 1 light to severe erythema and vasodilation . no erosion of mucosa 2 severe erythema and vasodilation . erosion of superficial aspects of mucosa leaving denuded areas . decreased stippling of mucosa . 3 formation of off - white ulcers in one or more places . ulcers may have a yellow / gray due to pseudomembrane . cumulative size of ulcers should equal about ¼ of the pouch . severe erythema and vasodilation . 4 cumulative seize of ulcers should equal about ½ of the pouch . loss of pliability . severe erythema and vasodilation . 5 virtually all of pouch is ulcerated . loss of pliability ( pouch can only partially be extracted from mouth ) a score of 1 - 2 was considered to represent a mild stage of the disease , whereas a score of 3 - 5 was considered to indicate moderate to severe mucositis . following visual scoring , a photograph was taken of each animal &# 39 ; s mucosa using a standardized technique . at the conclusion of the experiment , all films were developed and the photographs randomly numbered . at least two independent trained observers graded the photographs in blinded fashion using the above - described scale ( blinded scoring ). statistical differences between treatment groups were determined using student &# 39 ; s t - test , mann - whitney u test and chi - square analysis with a critical value of 0 . 05 . the results of the control and ip experiments are shown in fig1 - 4 . the data in fig1 show the mean mucositis score as a function of days after exposure to radiation for control hamster and hamsters treated with 1 mm and 5 mm of resveratrol ( ip administration ). as illustrated in fig2 ., treatment with resveratrol reduced the severity of mucositis compared to the control . treatment with 1 mm resveratrol was more effective than treatment with 5 mm of resveratrol . the percentage of days where hamsters had a mucositis score of less than three was reduced from 46 . 0 % for the control to 31 . 2 % for treatment with 5 mm and to 21 . 6 % for treatment with 1 mm of resveratrol ( fig3 ). fig4 lists the individual scores for each hamster in groups 1 - 3 , as defined above , as a function of time . the results of the experiments on topical application of resveratrol , although not statistically significant , indicated a trend of efficacy . compounds of formula i above can be synthesized by methods known in the art , for example , by the methods of moreno - manas et al . anal . quim . 1985 , 81 : 157 - 161 ; 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