| Abstract: |
In these studies the extent of the requirement for 5-methyltet-rahydrofolate 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 Vmax for the high-affinity system transporting 5-substituted reduced folates and methotrexate. They also exhibited reduced saturability for methotrexate influx (3-fold higher Km), but not for influx of 5-formyltetrahy-drofdlate 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-formyrtetrahydrofolate, and following reversion to a more transport-proficient phenotype. © 1985, American Association for Cancer Research. All rights reserved. |
| Keywords: |
nonhuman; methotrexate; cell proliferation; mouse; animal; mice; animal model; in vitro study; mice, inbred c57bl; drug receptor binding; drug accumulation; leukemogenesis; tumor cell; folic acid; drug metabolism; radioisotope; neoplasm transplantation; leucovorin; pharmacokinetics; mice, inbred dba; 5 methyltetrahydrofolic acid; leukemia l1210; priority journal; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; leukemia l 1210; blood and hemopoietic system; methotrexate h 3; folinic acid h 3
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