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 homologous recombination (HR) defective tumours in a human patient, the method comprising;
 administering a therapeutically effective amount of a compound which inhibits PARP-1 to a human patient.   
     
     
         34 . The method of  claim 33  wherein the compound which inhibits PARP-1 is selected from the group consisting of benzimidazole-carboxamides, quinazolin-4-[3H]-ones and isoquinolone derivatives. 
     
     
         35 . The method of  claim 34  wherein the compound which inhibits PARP-1 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 gene that mediates 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, RADS, FEN-1, Mus81, Emel, DDS1 and BARD. 
     
     
         37 . The method of  claim 33  wherein the cancer is selected from the group consisting of lung, colon, pancreatic, gastric, ovarian, cervical, breast and prostate cancer. 
     
     
         38 . A method of treatment of gene-linked hereditary cancer which is defective in homologous recombination (HR) in a human patient with a familial predisposition to said cancer, the method comprising;
 administering a therapeutically effective amount of a compound which inhibits PARP-1 to a human patient.   
     
     
         39 . The method of  claim 38  wherein the compound which inhibits PARP-1 is selected from the group consisting of benzimidazole-carboxamides, quinazolin-4-[3H]-ones and isoquinolone derivatives. 
     
     
         40 . The method of  claim 38  wherein the compound which inhibits PARP-1 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. 
     
     
         41 . The method of  claim 38  wherein the gene that mediates 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, RADS, FEN-1, Mus81, Emel, DDS1 and BARD. 
     
     
         42 . The method of  claim 38  wherein the cancer is selected from the group consisting of lung, colon, pancreatic, gastric, ovarian, cervical, breast and prostate cancer. 
     
     
         43 . A method of treatment of breast cancer in a human patient having one functional allele of BRCA1 or BRCA2, the method comprising;
 administering a therapeutically effective amount of a compound which inhibits PARP-1 to a human patient   
     
     
         44 . The method of  claim 43  wherein the PARP inhibitor is selected from the group consisting of benzimidazole-carboxamides, quinazolin-4-[3H]-ones and isoquinolone derivatives. 
     
     
         45 . The method of  claim 44  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.