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Rescue of Human Lymphoid Cells from the Effects of Methotrexate in Vitro¹

Department of Biochemistry, College of Medicine, University of Iowa, Iowa City, Iowa 52242

In protection experiments (5-formyltetrahydrofolate or 5-methyltetrahydrofolate added to cultures in vitro at the same time as methotrexate), 5-methyltetrahydrofolate afforded the same degree of protection as did formyltetrahydrofolate for phytohemagglutinin-stimulated peripheral blood lymphocytes and for methotrexate-resistant (R) and methotrexate-sensitive (S) sublines of CCRF-CEM. Either reduced folate at 100 µM protected phytohemagglutininstimulated lymphocytes or CCRF-CEM-S against 1 µM methotrexate almost completely, against 10 µM methotrexate partially, but not against 100 µM methotrexate. For CCRF-CEM-R 100 µM reduced folate partially protected against 10 µM methotrexate but did not protect against 100 µM methotrexate.

In rescue experiments, cells were exposed in vitro to methotrexate for a 1-hr period, washed, and then resuspended in conditioned medium containing the rescue agent. Again 5-methyltetrahydrofolate equalled 5-formyltetrahydrofolate in efficacy. Either reduced folate at 5 µM rescued phytohemagglutinin-stimulated lymphocytes or CCRF-CEM-S from 50 µM methotrexate, and 500 µM concentrations of either agent rescued CCRF-CEM-S from 500 µM methotrexate, CCRF-CEM-R is not rescued from 500 µM methotrexate (1 hr) by 500 µM agent.

The in vivo rescue of cells after high-dose methotrexate administration is more adequately modeled in vitro by rescue experiments than by protection experiments.

¹ This work was supported by USPHS Research Grant CA 14230 from the National Cancer Institute, NIH.

² To whom requests for reprints should be addressed.

Received 4/10/78. Accepted 8/ 8/78.