Enhancement of alkylating agent activity in vitro by PD 128763, a potent poly(ADP-ribose) synthetase inhibitor.
The ability of DNA repair inhibitors to potentiate alkylating agent cytotoxicity was explored with PD 128763, a dihydroisoquinolinone known to effectively inhibit poly(ADP-ribose) synthetase. The cytotoxic activity of streptozotocin in L1210 leukemia cells was maximally potentiated (7-fold decrease in IC50) under conditions of 24 hr exposure to PD 128763 following treatment with the alkylating agent for 1 hr. Similar treatment conditions resulted in a much greater effect (36-fold enhancement in activity) for the 2-nitroimidazole RSU 1069. In contrast, 3-aminobenzamide was only weakly effective at enhancing activity of either streptozotocin or RSU 1069 (2-3 fold potentiation). However, PD 128763 was ineffective at potentiating the cytotoxicity of the bifunctional alkylating agents carmustine (BCNU) and lomustine (CCNU). Our results are consistent with a role for (poly-ADP) ribosylation in the repair of monofunctional alkylating agent damage. This study supports further exploration of the combination of PD 128763 and RSU 1069 as a potentially useful chemotherapeutic regimen.
Sebolt-Leopold
J S
JS
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48105.
Scavone
S V
SV
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D002330:Carmustine / Q000494:pharmacology; D004357:Drug Synergism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D007939:Leukemia L1210; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013311:Streptozocin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C068870:3,4-dihydro-5-methyl-1(2H)-isoquinolinone; D013311:Streptozocin; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D002330:Carmustine