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- Title
High-dose intravenous zidovudine with 5-fluorouracil and leucovorin. A phase I trial.
- Authors
Posner, Marshall R.; Darnowski, James W.; Weitberg, Alan B.; Dudley, Michael N.; Corvese, Donna; Cummings, Frank J.; Clark, Jefery; Murray, Connie; Clendennin, Neil; Bigley, Joseph; Culabresi, Paul; Posner, M R; Darnowski, J W; Weitberg, A B; Dudley, M N; Corvese, D; Cummings, F J; Clark, J; Murray, C; Clendennin, N
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>Based on the results of preclinical studies, plasma zidovudine levels greater than those achieved at the maximal dose (133 microns) 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.
- Publication
Cancer (0008543X), 1992, Vol 70, Issue 12, p2929
- ISSN
0008-543X
- Publication type
journal article
- DOI
10.1002/1097-0142(19921215)70:12<2929::AID-CNCR2820701233>3.0.CO;2-W