Abstract
These studies extend the utility of assays for antifolate activity based on UdR incorporation into DNA. Indirect assay of UdR incorporation was used for comparison with drug uptake kinetics and with the extent of metabolic effectiveness of MTX and DDMP on WIL-2 cells. The immediate inhibition of UdR incorporation by DDMP was contrasted with the slower onset of inhibition by MTX. Notably, DDMP established a steady state of inhibition of UdR incorporation into DNA within 5 sec of its addition to WIL-2 cell cultures. Similar experiments were conducted to examine the conditions required to establish and maintain the metabolic toxicity of MTX in WIL-2 cells and human leukemic cells. A rationale is suggested for maintenance of MTX utilizing low doses of MTX or the lipid-soluble antifolate, DDMP. This approach may increase the selectivity of MTX based protocols, and have special efficacy for treatment of tumors of the central nervous system.
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