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The Effect of Vincristine on Methotrexate Uptake and Inhibition of DNA Synthesis by Human Lymphoblastoid Cells

Medicine Branch, National Cancer Institute, Bethesda, Maryland 20014

Vincristine (VCR) has been shown to enhance the transport of methotrexate (MTX) in animal systems and in acute myelogenous leukemia cells in vitro. In this report, the uptake of MTX and the effect of VCR were studied in two human lymphoblastoid cell lines grown in tissue culture. The effect of VCR on MTX suppression of deoxyuridine incorporation into DNA by these cell lines was also investigated.

The data indicate that an extracellular VCR concentration achievable following conventional single i.v. doses used clinically (0.1 µM) failed to enhance total intracellular MTX accumulation in either cell line at either conventional (1 µM) or "high-dose" (100 µM) extracellular MTX concentrations. An extracellular VCR concentration not achievable clinically (10 µM) did enhance total intracellular MTX at both MTX concentrations in both cell lines. However, neither VCR concentration (0.1 or 10 µM) enhanced the ability of MTX to suppress the incorporation of deoxyuridine into DNA, thought to be of vital importance to the antitumor effect of MTX. However, maximal suppression of deoxyuridine incorporation into DNA by MTX alone may have precluded detection of a VCR effect.

The results suggest that individual tumor thresholds exist for the MTX-VCR interaction and suggest that the empiric addition of VCR to clinical trials MTX, especially in the high-dose protocols currently being investigated, may be unwarranted. Further studies with a variety of human tumors are indicated to define more clearly the MTX-VCR interaction and its applicability to clinical trials.

¹ To whom requests for reprints should be addressed.

Received 12/27/76. Accepted 5/26/77.