METABOLIC AND RADIOLYTIC REDUCTION OF 4-ALKYLAMINO-5-NITROQUINOLINE BIOREDUCTIVE DRUGS - RELATIONSHIP TO HYPOXIA-SELECTIVE CYTOTOXICITY

The 4-alkylamino-5-nitroquinolines (5NQs) are a new series of bioreduc tive drugs that exhibit varying degrees of selective toxicity (up to 6 0-fold) under hypoxic conditions in cell culture. This study tested th e hypothesis that differences in hypoxia-selective cytotoxicity in thi s series reflect differences in the efficiency with which oxygen inhib its metabolic reduction. The products of reduction of six 5NQs were ch aracterized and rates of reduction compared in aerobic and hypoxic AA8 cells. The major stable products of both radiolytic and metabolic red uction under anoxic conditions were the corresponding amines, which we re not responsible for the toxicity of the parent nitro compounds. Met abolism of each compound was inhibited completely in aerobic cells, in dicating that differences in hypoxia-selective toxicity in this series are not due to variations in efficiency as substrates for oxygen-inse nsitive nitro reduction. Rates of hypoxic metabolism correlated broadl y with hypoxia-selective cytotoxicity; the 5NQ derivatives with high r ates of hypoxic metabolism had good hypoxia-selective cytotoxicity, wh ereas the compounds with low rates of reduction (the 3,6-dimethyl and 8-methylamino compounds; 3,6diMe-5NQ and 8NHMe-5NQ) were non-selective . Low rates of drug-induced oxygen consumption by 3,6diMe-5NQ and 8NHM e-5NQ in respiration-inhibited cells confirmed that these compounds ar e poor substrates for enzymatic nitro reduction. While there was an ov erall correlation between one-electron reduction potential at pH7 (E(1 )(7)) and rate of metabolic reduction, the relatively high E(1)(7) of 3,6diMe-5NQ (-367 mV) indicates that rates of reduction, and hypoxic s electivity of cytotoxicity, cannot be predicted from reduction potenti al alone. 3,6diMe-5NQ and 8NHMe-5NQ are cytotoxic through a non-biored uctive mechanism, the variable contribution of which may underlie the differences in hypoxia-selective cytotoxicity within this series of bi oreductive drugs.