Potentiation of antineoplastic drugs in vitro and in vivo by DNA intercalating bioreductive agents

Abstract

AbstractThree recently synthesized 2‐nitroimidazole‐linked acridine DNA intercalators (NLA‐1, NLA‐2, and NLA‐4) have been studied as potentiators of the cytotoxic effect of melphalan (L‐PAM), 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU), cis‐diamminedichloroplatinum (II) (cis‐DDP), and doxorubicin in V79 cells. In vivo studies have also been performed with all three sensitizers and L‐PAM, while NLA‐1 alone was examined for potentiation of cis‐DDP, using C3H/HEJ mice, bearing a murine ovarian tumor. Significant chemosensitization was observed in vitro with L‐PAM, CCNU, and cis‐DDP after hypoxic preincubation treatment of the cells (37°C) at negligible concentrations of each sensitizer, while inhibition was observed with doxorubicin. Long hypoxic preexposure times at relatively low sensitizer doses were more effective than short hypoxic preexposure times at high sensitizer doses for potentiation. Glutathione depletion studies in vitro with diethyl maleate (DEM) showed that only less than half of the enhanced toxicity observed with NLA‐1 or NLA‐4 and L‐PAM is due to glutathione depletion by the sensitizer. The LD50/35 value in C3H/HEJ mice for NLA‐1, NLA‐2, and NLA‐4 was 45, 25, and 63 mg/kg, respectively. Significant antitumor effect was observed in vivo when 25 mg/kg of NLA‐1 was administered i.p. to tumor‐bearing mice 2 hr before L‐PAM administration (2.5 mg/ kg, i.p.). With this combination pattern of sensitizer:antineoplastic drug, 50% cures were observed in mice followed for >150 days; no long‐term survivors were observed with L‐PAM therapy alone. © 1993 Wiley‐Liss, Inc.