Enhancement of melphalan cytotoxicity in vivo and in vitro by inhibitors of poly (ADP-ribose) polymerase.
In these preliminary experiments, we have found enhanced cell killing by the bifunctional alkylating agent L-phenylalanine mustard (L-PAM) in the presence of inhibitors of poly (ADP-ribose) polymerase (ADPRP) in vitro. In vivo enhancement of the tumoricidal effects of L-PAM was observed with the ADPRP inhibitor nicotinamide (1000 mg/kg), although enhanced myelosuppression was also demonstrated. Nicotinamide also increased the plasma elimination half-life of L-PAM by a factor of at least 2. This alteration of L-PAm pharmacokinetics makes it difficult to assess the role that ADPRP inhibition plays in the enhancement of L-PAM tumor cell killing in vivo.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D009244:NAD+ Nucleosidase / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009536:Niacinamide / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013997:Time Factors
D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D002110:Caffeine; C025160:3-aminobenzamide; D009244:NAD+ Nucleosidase; D008558:Melphalan