NLCQ-1 (NSC 709257): exploiting hypoxia with a weak DNA-intercalating bioreductive drug

The development of weak DNA-intercalating bioreductive compounds is a new strategy to ensure DNA affinity high enough to produce toxicity yet low enough to permit efficient extravascular diffusion and penetration to hypoxic tumor tissue, as has been exemplified by the lead compound 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257). Indeed, because of its weak DNA-binding, NLCQ-1 demonstrates significant hypoxic selectivity in several rodent and human tumor cell lines that can be increased up to 388-fold with 4.5 h exposure. In vitro reduction studies suggest that cytochrome P450 and b(5) reductases play a significant role in NLCQ-1 bioreductive activation. NLCQ-1 synergistically enhances the effect of radiation against hypoxic cells in vitro and murine tumors in vivo and optimizes the effect of radioimmunotherapy in human xenografts. Importantly, NLCQ-1 substantially enhances, in a schedule-dependent manner, the antitumor effect of alkylating agents, as well as 5-fluorouracil and paclitaxel against murine tumors and human xenografts, without a concomitant enhancement in bone marrow or hypoxia-dependent retinal toxicity. In addition, NLCQ-1 exhibits good stability in human plasma and favorable pharmacokinetics in mice. The synthesis of NLCQ-1 has been successfully scaled-up and its excellent recovery from biological fluids has been established. Because of these results and the fact that NLCQ-1 compares favorably with the frontrunner, bioreductive compound tirapazamine, NLCQ-1 is about to enter a Phase I clinical trial.