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• W2100000050 abstract "Summary The relationship of cell permeability phenomena to the selective activity of methotrexate (MTX) during therapy of the L1210 leukemia was examined. Drug uptake and loss in normal tissue (small intestine) and L1210 cells in the peritoneal cavity were measured following the administration of single s.c. doses of 3, 0.3, and 0.03 mg of MTX per kg. Within 1 hr after a dose of 3 mg/kg, drug levels in L1210 cells and small intestine were, respectively, four- and sixfold greater than the dihydrofolate reductase content. After 0.3 mg/kg, the initial rate of uptake in both cases was similar, but the intracellular level exceeded the enzyme content in only L1210 cells. After a dose of 0.03 mg/kg, uptake was almost nonexistent in small intestine but still appreciable in L1210 cells. Free MTX was lost from small intestine far more rapidly then from L1210 cells. After 3 mg/kg, drug level in intestine fell to enzyme level in 3 hr, but in L1210 cells the fall required 18 to 20 hr. After a dose of 0.3 mg/kg, approximately 8 hr were required for the drug level in L1210 cells to reach enzyme level. Following a dose of 3 mg of MTX per kg, administered i.p., initial uptake was more rapid and reached higher intracellular levels in both L1210 cells and small intestine when compared to that which occurred following the same dose given s.c. Drug also persists in L1210 cells in the peritoneal cavity, but not small intestine, for a somewhat longer period of time following i.p. administration. Uptake and loss of MTX following a dose of 3 mg/kg s.c. is the same in small intestine from normal and leukemic mice. Incorporation of deoxyuridine- 3 H into DNA of both small intestine and L1210 cells was almost completely inhibited by 1 hr after a s.c. dose of 3 mg/kg. Resumption of incorporation required 4 hr in small intestine but 14 to 16 hr in L1210 cells. The results reveal a far greater persistence of free MTX and a more sustained metabolic effect in L1210 cells than in small intestine. This is attributed, at least in part, to a more effective influx of drug in L1210 cells at low plasma levels." @default.
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• W2100000050 title "Differential cell permeability and the basis for selective activity of methotrexate during therapy of the L1210 leukemia." @default.
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