Bioreductive activation as a factor in the use of quinone antibiotics in cancer chemotherapy

Bioreductive activation appears to be important for the antineoplastic activity of quinone antibiotics. Because the activated intermediates are extremely reactive, they alkylate before diffusing from the cell in which they are produced; the activation and inactivation processes occurring within a cell therefore determine toxicity to that cell. The bioreductive activation of the antineoplastic quinones has been examined extensively using purified enzyme systems, sonicated cells systems, and intact cells. The activation and metabolism of these drugs by tumors cells is a complex process which involves several enzyme systems and is influenced by intracellular pH and O/sub 2/ levels. Some drugs have several possible reactive sites and can produce several different, potentially toxic lesions. The relative cytoxicity of different quinones to hypoxic and aerobic cells and the potency of the agents relative to one another appear to reflect differences in the intracellular activation and metabolism of the drugs. Certain agents, eg. mitomycin C and porfiamycin, are selectively toxic to hypoxic cells in vitro. The biological bases for this selective cytoxicity, the nature of the toxic lesions, and the possible role of these and similar bioreductive alkylating agents as adjuncts to radiotherapy are being actively explored