Modulation versus rescue of antimetabolite toxicity by salvage metabolites administered by continuous infusion

A system has been developed for the long-term continuous intravenous infusion of chemotherapeutic agents into unrestrained mice which allows new approaches to the toxicological and chemotherapeutic evaluation of antimetabolites. In mice, the concurrent infusion of thymidine and a source of preformed purine reversed both the toxicity and antitumor activity of MTX comparable to what was previously observed in cell culture. The infusion of thymidine alone, however, also blocked the toxicity of MTX without interfering with antitumor activity. A comparison of leucovorin rescue versus the utilization of thymidine plus preformed purine indicated that these salvage metabolites were as effective as leucovorin in reducing the toxicity of high-dose MTX while retaining antitumor activity.