This project is intended to improve therapeutic efficacy of anthracyclines (Adriamycin, daunorubicin, etc.), AZQ, and related agents by altering their metabolic transformations in animals. In tumor bearing mice, anthracycline drugs will be given in combination with allopurinol which inhibits xanthine oxidase, an enzyme that converts the anthracyclines to aglycones. The same system also metabolizes AZQ and it will be tested in combination with allopurinol in mice with tumors (L1210, P388, etc.). AZQ specifically designed for chemotherapy of brain tumors, will be tested in animals with rescue agents that inactivate the drug systemically (to reduce host toxicity) but have little or no effect on AZQ in brain tumors. Associated with these studies, the effects of rescue agents in bone marrow cells with be tested by spleen colony assays. The pharmacokinetics and metabolism of AZQ in animals will be described. The interactions of labile intermediary products of biotransformation of anthracyclines, AZQ, and similar agents with DNA will be investigated with respect to cross-links and interstrand damage. These effects on DNA will be evaluated with DNA polymerase alpha.
