COMBINATION EFFECTS OF POLY(ADP-RIBOSE) POLYMERASE INHIBITORS AND DNA-DAMAGING AGENTS IN OVARIAN TUMOR-CELL LINES - WITH SPECIAL REFERENCE TO CISPLATIN

The effects of the poly(ADP-ribose) polymerase inhibitors 4-amino-1,8- naphthalimide (4-ANI), 6(5H)-phenanthridinone (PHD), 1,5-isoquinolined iol (IQD), 3-aminobenzamide (3-AB) or 4-hydroxyquinazoline (4-HYA) on the cytotoxicity of cisplatin were investigated. The human ovarian tum or cell lines SK-OV-3 and OAW 42 and the rat ovarian tumor cell line O -342 as well as its cisplatin(DDP)-resistant subline O-342/DDP were us ed. Cytotoxicity was determined with the (4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. 1-Methyl-3-nitro-1-nitrosog uanidine (MNNG) plus its respective combinations with poly(ADP-ribose) polymerase inhibitors served as positive controls. In addition, the a lkylating agents L-threitol-1,4-bismethanesulfonate (DHB) and 1,3-bis (2-chloroethyl)-1-nitrosourea (carmustine) as well as two other DNA-re pair inhibitors caffeine and theophylline were included in the investi gations. The cytotoxicity of cisplatin could not be increased by 4-ANI , PHD, IQD, 4-HYA or 3-AB in any cell line investigated, while it was increased by caffeine in lines O-342/DDP and SK-OV-3 as well as by the ophylline in lines O-342/DDP, SK-OV-3 and OAW 42. The cytotoxicity of MNNG was increased by combination with 4-ANI, PHD, IQD, 4-HYA, 3-AB or theophylline for all lines except OAW42; in the latter line, only 4-A NI, PHD and IQD increased MNNG cytotoxicity. The cytotoxicity of DHB w as increased by 4-ANI, PHD, 4-HYA, theophylline and caffeine in line O -342/DDP; by 4-HYA, theophylline and caffeine in line SK-OV-3; and by theophylline and caffeine in line OAW42. The cytotoxicity of carmustin e was increased only by 3-AB in two lines (SK-OV-3 and OAW 42). Result s are discussed with regard to different DNA-repair mechanisms.