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-isoquinolinediol (IQD), 3-aminobenzamide (3-AB) or 4-hydroxyquinazoline (4-HYA) on the cytotoxicity of cisplatin were investigated. The human ovarian tumor 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 used. Cytotoxicity was determined with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) plus its respective combinations with poly(ADP-ribose) polymerase inhibitors served as positive controls. In addition, the alkylating agents L-threitol-1,4-bismethanesulfonate (DHB) and 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine) as well as two other DNA-repair inhibitors caffeine and theophylline were included in the investigations. 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 theophylline 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-ANI, PHD and IQD increased MNNG cytotoxicity. The cytotoxicity of DHB was 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 carmustine was increased only by 3-AB in two lines (SK-OV-3 and OAW 42). Results are discussed with regard to different DNA-repair mechanisms.
Bernges
F
F
German Cancer Research Center, Heidelberg, Germany.
Zeller
W J
WJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002330:Carmustine / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011064:Poly Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors*; D051381:Rats; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D008769:Methylnitronitrosoguanidine; D011064:Poly Adenosine Diphosphate Ribose; D002945:Cisplatin; D002330:Carmustine