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Cytokinetic Comparison of Thymidine and Leucovorin Rescue of Marrow in Humans after Exposure to High-Dose Methotrexate¹

Department of Medicine T-006, University of California, San Diego, La Jolla, California 92093 [S. B. H.]; Division of Cytokinetics, Comprehensive Cancer Center for the State of Florida, Miami, Florida 33101 [A. K.]; and Sidney Farber Cancer Institute, Boston, Massachusetts 02115 [E. F., III]

The cytokinetics of marrow recovery were compared in patients receiving a standard exposure to high-dose methotrexate followed by either thymidine rescue, leucovorin rescue at the doses used in most clinical protocols (10 mg/sq m every 6 hr), or leucovorin rescue at a 5-fold higher dose rate (50 mg/sq m every 6 hr). Thymidine rescue initiated a prompt recovery of DNA synthesis, as detected by [³H]deoxycytidine incorporation, and progression of cells through the cell cycle monitored by flow cytometry, even in the presence of methotrexate levels that prevented initiation of rescue by the lower doses of leucovorin. Dose dependency for leucovorin in vivo in humans was suggested by the observation that the higher leucovorin dose rate was successful in initiating rescue within the first 24 hr, whereas the lower dose was not. Recovery of DNA synthesis is more rapid and/or complete with thymidine rescue than with either dose of leucovorin. Thymidine rescue was accomplished without requirement for purines over and above those present in plasma. These results suggest that the kinetics of marrow recovery is quite different for thymidine and leucovorin rescue.

¹ Supported in part by Research Grants CA23100, CA17979, CA06516, CA23688, and CA19589 from the National Cancer Institute. A preliminary report of this work was presented (15).

² To whom requests for reprints should be addressed.

Received 6/16/77. Accepted 1/12/79.