Enhancement of alkylating agent activity in vitro by PD 128763, a potent poly(ADP-ribose) synthetase inhibitor.

Abstract

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.

• Authors: J S Sebolt-Leopold, S V Scavone
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 22 Issue 3 Pg. 619-21 ( 1992) ISSN: 0360-3016 [Print] United States
• PMID: 1531221 (Publication Type: Journal Article)

Chemical References

• Alkylating Agents
• Isoquinolines
• Poly(ADP-ribose) Polymerase Inhibitors
• 3,4-dihydro-5-methyl-1(2H)-isoquinolinone
• Streptozocin
• 1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol
• Misonidazole
• Carmustine

Topics

• Alkylating Agents (pharmacology)
• Animals
• Carmustine (pharmacology)
• Drug Synergism
• In Vitro Techniques
• Isoquinolines (pharmacology)
• Leukemia L1210
• Misonidazole (analogs & derivatives, pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Streptozocin (pharmacology)
• Tumor Cells, Cultured