The suppression of DNA synthesis in host and tumor tissues by methotrexate has been monitored in mice by determining the in vivo incorporation of tritium-labeled deoxyuridine ([3H]UdR) into DNA. The duration of inhibition of [3H]UdR incorporation in normal tissues was related to the dose of methotrexate and was a direct function of plasma drug concentration. [3H]UdR incorporation recovered to 50% of pretreatment levels in bone marrow when plasma methotrexate concentration was 10-8 M or less, irrespective of the dose administered, while 50% recovery of DNA synthesis in intestinal epithelium was not observed until plasma methotrexate levels were 5 × 10-9 M or less. Ascitic L1210 leukemia cells did not fully return to pretreatment levels of [3H]UdR incorporation at any time, although a partial recovery of incorporation was noted at methotrexate ascitic fluid concentrations of approximately 10-8 M.
Bruce A. Chabner, Robert C. Young
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