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Different Effects of Vincristine on Methotrexate Uptake by L1210 Cells and Mouse Intestinal Epithelia in Vitro and in Vivo¹

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

A comparative study of the effect of vincristine on the intracellular level of methotrexate in murine tumor (L1210 cells) and normal proliferative tissue (small intestine) in vitro and in vivo is presented. During in vitro studies, vincristine did not alter the initial rate of methotrexate uptake by L1210 cells, but did produce an increase in the steady-state level of exchangeable drug. The magnitude of the increase was dependent upon the concentration of Vinca alkaloid (0.1 to 10 µM). A maximum increase of 125% occurred with vincristine concentrations of 10 µM or higher. In parallel studies in vitro, vincristine concentrations up to 40 µM had no effect on methotrexate uptake by isolated intestinal epithelial cells.

For in vivo studies, mice were given injections of methotrexate, 25 mg/kg i.p., and the concentration of folate analog in L1210 ascites and small intestine was monitored for 24 hr. In both tumor cells and small intestine, peak levels of methotrexate were attained at 40 min to 1 hr after injection. Exchangeable methotrexate above that bound to dihydrofolate reductase persisted for >24 hr in tumor cells and <12 hr in small intestine. Vincristine, 0.5 to 5.0 mg/kg i.p., administered 2.5, 1.5, or 0.5 hr prior to methotrexate or 6, 16, 24, or 32 hr after methotrexate had no effect on the pharmacokinetics for methotrexate in either tumor cells or normal tissue.

Treatment of mice bearing the L1210 leukemia with vincristine, 0.25 to 1.0 mg/kg i.p., prior to or together with methotrexate, 25 mg/kg i.p., produced no therapeutic gain other than that which could be explained from an additive effect of the two agents. However, delay of vincristine administration for several hr after methotrexate did produce therapeutic synergism. At a vincristine concentration of 0.5 mg/kg i.p., a maximum synergism (227% increased life span) was obtained when the interval between the two agents was 24 hr or longer. The synergistic effect was dose-dependent within the range of 0.25 to 1.0 mg/kg.

These data show that therapeutic synergism can result from the temporal use of vincristine and methotrexate. However, they raise the question of whether the mechanism for the synergism is related to the interaction between vincristine and methotrexate shown in vitro.

¹ This work was supported in part by Grants CA 08748, CA 18856, and CA 22764 from the National Cancer Institute and CH 26 from the American Cancer Society.

Received 3/10/78. Accepted 3/13/79.