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Methotrexate Rescue by 5-Methyltetrahydrofolate or 5-Formyltetrahydrofolate in Lymphoblast Cell Lines

Ludwig Institute for Cancer Research, Blackburn Building, University of Sydney, New South Wales 2006, Australia

The rescue of lymphocytes from methotrexate (MTX) growth inhibition by 5-methyltetrahydrofolate (5-methyl-THF) and 5-formyltetrahydrofolate (5-formyl-THF) has been studied. Rescue by 5-methyl-THF is selective for cells with high levels of homocysteine:5-methyl-THF methyl-transferase (methyltransferase). At MTX concentrations which inhibited growth 85% in both leukemic T-lymphocytes (CCRF-CEM) and Epstein-Barr-transformed B-lymphocytes (LAZ-007), 5 µM 5-formyl-THF rescued more effectively than did 5-methyl-THF, in either the presence or absence of the methyltransferase inhibitor, nitrous oxide. At less inhibitory MTX concentrations, both reduced folates rescued equally, except when methyltransferase was inhibited by nitrous oxide in which case 5-formyl-THF was clearly superior.

In the absence of nitrous oxide, both cell lines contained approximately equal amounts of methyltransferase. Some apparent differences in the rescue of these cell lines with 5-methyl-THF were attributable to their different sensitivity to MTX.

When metabolism of reduced folates was severely impaired by MTX and nitrous oxide, lymphocytes were rescued with 5-[methyl-¹⁴C]methyl-THF, and the uptake of ¹⁴C into DNA was measured. Incorporation was very low, indicating that cellular oxidation of 5-methyl-THF to 5,10-methylene-tetrahydrofolate is minimal even under forcing conditions.

MTX selectivity in vivo will be influenced by the level of methyltransferase in tumor and normal tissues.

¹ Present address: Department of Medicine, Clinical Sciences Building, Prince Henry Hospital, Little Bay, New South Wales 2036, Australia.

² To whom requests for reprints should be addressed.

Received 5/11/81. Accepted 11/ 5/81.

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