High‐dose intravenous zidovudine with 5‐fluorouracil and leucovorin. A phase I trial

Background. The inhibition of pyrimidine metabolism by 5‐fluorouracil (5‐FU) enhances the anti‐cancer effects of zidovudine (formerly called AZT) in in vitro and in vivo model systems without additive toxicity. Zidovudine‐induced DNA damage correlates with cytotoxicity. Methods. A Phase I trial of high‐dose continuous‐infusion intravenous zidovudine therapy in combination with 5‐FU and leucovorin therapy was performed. Eighteen patients with advanced malignant tumors were treated with 43 courses of oral leucovorin (50 mg every 4 hours); continuous‐infusion 5‐FU (800 mg/M²/day) for 72 hours (3 days); and zidovudine, begun 24 hours after the start of 5‐FU and leucovorin, for 48 hours, and terminating with the end of the 5‐FU infusion. Zidovudine plasma levels and zidovudine‐induced DNA damage were assessed. Results. Zidovudine administered in doses of 2–20 g/M²/day, added no obvious toxicity to the basic chemotherapeutic treatment with 5‐FU and leucovorin but resulted in a dose‐dependent biologic effect manifested by an increase in DNA strand breaks in peripheral blood cells. At doses greater than 15 g/M²/day, altered plasma kinetics of zidovudine were observed; plasma zidovudine levels increased dramatically in relation to the dose of zidovudine. Limitations in drug administration restricted administration of higher intravenous doses without achieving a maximally tolerated dose. No responses were seen in this heavily pretreated population. Conclusions. Based on the results of preclinical studies, plasma zidovudine levelds greter than those achieved at the maximal dose (133 μm) are required for increased anti‐cancer activity with 5‐FU. Additional studies using a bolus or rapid infusion as a method of achieving higher peak levels are indicated.