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Extent of the Requirement for Folate Transport by L1210 Cells for Growth and Leukemogenesis in Vivo¹

Memorial Sloan-Kettering Cancer Center, New York, New York 10021

In these studies the extent of the requirement for 5-methyltetrahydrofolate by L1210 cells for growth and leukemogenesis in vivo was addressed from the aspect of its cellular membrane transport. Growth characteristics and leukemogenesis in vivo were determined for parental and methotrexate-resistant L1210 cell variants with reduced capacity for folate coenzyme transport inward. These variants exhibited 6-, 16-, and 100-fold reductions compared to parental cells in influx V_max for the high-affinity system transporting 5-substituted reduced folates and methotrexate. They also exhibited reduced saturability for methotrexate influx (3-fold higher K_m), but not for influx of 5-formyltetrahydrofolate or 5-methyltetrahydrofolate. The reduced influx capacity in these variants correlated with their increased requirement for reduced folates during growth in vitro and with the ability of the variants to proliferate and develop leukemia in vivo. Lack of growth potential in vivo for one variant appears to reflect the inability for net intracellular accumulation of reduced folate per se, since growth of this variant could be restored by treatment of mice with folic acid, but not with 5-methyltetrahydrofolate or 5-formyltetrahydrofolate, and following reversion to a more transport-proficient phenotype.

¹ Supported in part by Grants CA 08748, CA 18856, and CA 22764 from the National Cancer Institute, and by Grant CH-26 from the American Cancer Society and the Elsa U. Pardee Foundation.

² To whom requests for reprints should be addressed, at Laboratory for Molecular Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Received 2/25/85. Revised 5/20/85. Accepted 6/13/85.

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