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Thymidine Requirements for the Rescue of Patients Treated with High-Dose Methotrexate¹

Department of Medicine, Cancer Center, and General Clinical Research Center of the University of California, San Diego, La Jolla, California 92093 [S. B. H., K. H., G. R. B.], and the Sidney Farber Cancer Institute, Boston, Massachusetts 02115 [E. F.]

A Phase I trial was conducted to determine the minimum dose of thymidine (dThd) required to rescue patients from a bolus infusion of methotrexate (3 g/sq m) when dThd was started 24 hr later and given by constant infusion until the serum methotrexate level was <5 x 10^-8 M. Twenty-six patients received 63 courses; four courses were inevaluable due to nephrotoxicity. The dThd dose was deescalated from 8.0 to 0.3 g/sq m/day. The incidence of toxicity due to inadequate rescue was quite variable, but the severity of toxicity was related to dThd dose. Severe toxicity occurred on 25% of courses where dThd rescue doses 1.0 g/sq m/day were used, compared with a 6% incidence with dThd doses >1.0 g/sq m/day (p < 0.05). At dThd doses of <1 g/sq m/day, marrow recovery was often very delayed, and macrocytosis and hypersegmented polymorphonuclear WBC developed. At dThd doses that provided adequate rescue, serum dThd levels were increased only marginally, indicating a very steep dose-response relationship for dThd rescue of marrow. Although methotrexate can inhibit de novo purine synthesis, satisfactory rescue was achieved without requirement for exogenous purines, and no effect of dThd on purine production was detected in two patients who received dThd (8 g/sq m) over 24 hr while on a purine-free diet. There was no change in serum uric acid or in total urinary uric acid and oxypurine excretion. This study demonstrates that the minimum dose of dThd required for rescue is in the range of 1 g/sq m/day. The 8-fold larger doses used in previous studies of dThd rescue may have obscured potential selectivity based on differential utilization of dThd by normal and malignant cells.

¹ Supported by USPHS Grants CA23100, CA23334, and RR00827. A preliminary report of this study has been presented (15).

² To whom requests for reprints should be addressed, at the Department of Medicine T-006, University of California, San Diego, La Jolla, Calif. 92093.

Received 5/29/79. Accepted 2/13/80.

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