Vincristine inhibits the exit pump for methotrexate in Ehrlich ascites tumor cells in vitro

M. J. Fyfe, I. D. Goldman

Research output: Contribution to journalArticle

Abstract

Methotrexate (MTX) and folates share a carrier transport process with unique energetics in many mammalian cells. Metabolic inhibitors increase the intracellular (IC) electrochemical potential (ECP) for MTX suggesting an energy dependent process driving MTX out of the cell. Because vincristine (VCR) increases net uptake of MTX into tumor cells, studies were undertaken to determine the mechanism by which this occurs. When VCR is added to Ehrlich ascites tumor cells which are at the steady state (SS) with 3H MTX, net uptake of MTX is augmented within 3 min and a higher SS IC MTX level is achieved. The unidirectional (uni)influx of MTX is unchanged, the uni efflux is slowed, there is a small increase in nonexchangeable IC MTX and a large increase in exchangeable IC MTX. Cell volume and chloride distribution ratio are unchanged. This suggests that VCR increases the ECP for IC MTX, an effect dependent on the VCR concentration over a range of at least 5 to 50 uM. The VCR effect is rapidly reversible after removal of extracellular VCR; net accumulation of IC MTX is reduced, the uni efflux increased, and the VCR induced bound fraction eliminated. Stimulation of net MTX uptake by VCR is partially reversed by addition of glucose, while the stimulatory effect of azide is completely reversed by glucose. These data suggest that VCR inhibits an energy dependent exit process for MTX and that the basis of this effect is due, at least in part, to an inhibition of aerobic metabolism.

Original languageEnglish (US)
Number of pages1
JournalFederation Proceedings
Volume32
Issue number3 (I)
StatePublished - Jan 1 1973
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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