5-methyltetrahydrofolate and Leukemia-L5178

We have increased significantly the survival time of DBA/2 mice bearing methionine-dependent L1210 or L5178Y leukemia cells by i.p. administration of lethal doses of methotrexate (five daily doses of 25 mg/kg body weight) followed by rescue with 5-methyl tetrahydrofolate (five daily doses of 20 mg/kg body weight). The mice were maintained on a semipurified choline- and cyst(e)ine-free diet containing 0.32% L-methionine. We further increased significantly the survival time of the treated animals bearing L5178Y cells, but not those bearing L1210 cells, by substitution of 0.86% DL-homocystine for the methionine in the diet. We have examined the effects of both diets in mice treated with methotrexate and 5-methyl tetrahydrofolate, singly and in combination, on the concentrations of S-adenosylmethionine and S-adenosylhomocysteine in the liver, a tissue highly active in the metabolism of these amino acids. The substitution of homocystine for methionine in the diet of untreated animals led to a significant increase in S-adenosylhomocysteine and decrease in S-adenosylmethionine in the liver, with a resultant profound decrease in the ratio of S-adenosylmethionine to S-adenosylhomocysteine which was not further altered significantly by administration of methotrexate.

Topics: Animals; Diet; Homocysteine; Homocystine; Kinetics; Leukemia L1210; Leukemia L5178; Leukemia, Experimental; Liver; Male; Methotrexate; Mice; Mice, Inbred DBA; S-Adenosylhomocysteine; S-Adenosylmethionine; Tetrahydrofolates

The ability of CF to protect cells from methotrexate toxicity was measured in a series of murine lymphoma cells of varying degrees of sensitivity to methotrexate. The cells that were the most resistant to methotrexate showed the least degree of protection from methotrexate cytotoxicity. The extent of protection afforded by CF was found to correlate with the capacity of the cells to take up C14-5-methyltetrahydrofolate. That is, the cells with the lowest extent of uptake of reduced folate were afforded the least degree of protection from methotrexate by CF.

Topics: Animals; Biological Transport; Cell Line; Cell Survival; Kinetics; Leucovorin; Leukemia L1210; Leukemia L5178; Leukemia, Experimental; Methotrexate; Mice; Tetrahydrofolates