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Thymidine Rescue of High-Dose Methotrexate in Humans¹

Department of Medicine, Sidney Farber Cancer Institute [S. B. H., W. D. E., E. F.], and Pathology, Harvard Medical School [A. K.], Boston, Massachusetts 02115

Thymidine rescue was administered following 63 courses of high-dose methotrexate in 20 patients. In the first part of this study, the methotrexate was given as a 24-hr infusion and the dose was escalated from 0.14 to 8.54 g/sq m; in the second part, methotrexate was infused to maintain a serum concentration of 15 µM for 30, 36, or 40 hr. Thymidine rescue was started immediately after the end of the methotrexate infusions, and consisted of 8 g/sq m/day for 3 days or until serum methotrexate was below a toxic level. Mucositis and myelosuppression were the major toxicities. Neither was dose related. Serum methotrexate levels were proportional to the logarithm of the methotrexate dose. There was a mean 6-fold increase in thymidine concentration during rescue. However, thymidine levels prior to and during rescue were not related to the incidence of subsequent toxicity. Recovery of DNA synthesis in bone marrow cells was evident by nucleoside precursor incorporation at 24 hr after the start of rescue. Two of 16 evaluable patients achieved partial responses. This study indicates that thymidine is an effective rescue agent for high-dose methotrexate in humans.

¹ This investigation was supported by Grants CA-17979, CA-06516, CA-20008, and CA-19589 from the National Cancer Institute.

² To whom reprint requests should be addressed, at Department of Medicine M-013, University of California, San Diego, La Jolla, Calif. 92093.

Received 6/20/77. Accepted 11/10/77.