Use of RNAI Inhibiting PARP Activity for the Manufacture of a Medicament for the Treatment of Cancer

Abstract

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination.

1 - 32 . (canceled) 
     
     
         33 . A method of treatment of cancer cells defective in homologous recombination (HR) in a human patient, the method comprising;
 administering to the patient a therapeutically effective amount of a compound which inhibits PARP-1.   
     
     
         34 . The method of  claim 33  wherein the PARP inhibitor is selected from the group consisting of benzimidazole-carboxamides, quinazolin-4-[3H]-ones and isoquinolone derivatives. 
     
     
         35 . The method of  claim 34  wherein the PARP inhibitor is selected from the group consisting of 2-(4-hydroxyphenyl)benzimidazole-4-carboxamide, 8-hydroxy-2-methylquinazolin-4-[3H]one, 6(5H)phenanthridinone, 3-aminobenzamide, benzimidazole-4-carboxamides and tricyclic lactam indoles. 
     
     
         36 . The method of  claim 33  wherein the cancer cells have defect in a gene encoding a protein involved in HR. 
     
     
         37 . The method of  claim 36  wherein the human patient has one functional allele of said gene, said functional allele being lost in the cancer cells. 
     
     
         38 . The method of  claim 33  wherein the gene encoding a protein involved in HR is selected from the group consisting of XRCC1, CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51B, RAD51C, RAD51D, DMC1, XRCC2, XRCC3, BRCA1, BRCA2, RAD52, RAD54, RAD50, MRE11, NBS1, WRN, BLM, Ku70, Ku80, ATM, ATR, chkl, chk2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1, RAD9, FEN-1, Mus81, Emel, DDS1 and BARD. 
     
     
         39 . The method of  claim 33  wherein the cancer cells are selected from the group consisting of lung, colon, pancreatic, gastric, ovarian, cervical, breast and prostate cancer. 
     
     
         40 . The method of  claim 33  wherein the cancer cells are selected from the group consisting of renal, liver, and bladder cancer. 
     
     
         41 . The method of  claim 33  wherein the cancer is gene-linked hereditary cancer. 
     
     
         42 . The method of  claim 41  wherein the cancer is breast cancer. 
     
     
         43 . The method of  claim 33  wherein the cancer cells to be treated are defective in BRCA1 expression. 
     
     
         44 . The method of  claim 33  wherein the cancer cells to be treated are defective in BRCA2 expression. 
     
     
         45 . The method of  claim 33  comprising determining the inhibition of PARP-1 in said individual following said administration. 
     
     
         46 . The method of  claim 33  comprising identifying a patient with a familial predisposition to said cancer and administering said compound to said patient. 
     
     
         47 . The method of  claim 33  wherein the daily dosage of said compound is sufficient to induce apoptosis in the cancer cells without affecting normally dividing cells in the human patient. 
     
     
         48 . The method of  claim 33  wherein the daily dosage of said compound is up to 20 mg/Kg body weight. 
     
     
         49 . The method of  claim 48  wherein the daily dosage of said compound is more than 2 mg/Kg body weight. 
     
     
         50 . The method of  claim 33  wherein the compound which inhibits PARP-1 is not administered in combination with radio- or chemo-therapy. 
     
     
         51 . The method of  claim 33  wherein the compound which inhibits PARP-1 is administered in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.