Teniposide (VM-26) - and etoposide (VP-16-213) -induced augmentation of methotrexate transport and polyglutamylation in Ehrlich ascites tumor cells in vitro
Yalowich, J.C.; Fry, D.W.; Goldman, I.D.
Cancer Research 42(9): 3648-3653
1982
ISSN/ISBN: 0008-5472 PMID: 6179605 Document Number: 193609
Teniposide (VM-26) and etoposide (VP-16-213) were evaluated for their effects on methotrexate transport and metabolism in Ehrlich ascites tumor cells in vitro. VM-26 (10 .mu.M) does not alter influx of methotrexate but slows efflux of the drug which leads to an increase in the steady-state level of exchangeable antifolate. VM-26 stimulation of net methotrexate transport occurs within 5 min of exposure of cells to VM-26 concentrations of from 10-50 .mu.M; removal of extracellular VM-26 results in a rapid and complete reversal of this effect. As extracellular VM-26 is raised to 50 .mu.M, the progressive rise is net methotrexate uptake observed is due not only to elevated exchangeable antifolate but to an enlarged nonexchangeable pool of intracellular drug as well, a major portion of which is methotrexate polyglutamyl derivatives. VM-26 does not alter the intracellular water or the Cl- distribution ratio. Glucose partially reverses the stimulatory effect of VM-26, but to a lesser extent than glucose reversal of the vincristine-induced stimulation of net methotrexate transport. VP-16-213 also stimulates net methotrexate transport in a manner qualitatively similar to that of VM-26. However, 100 .mu.M VP-16-213 is required to yield the same quantitative stimulation as seen for 10 .mu.M VM-26. VP-16-213-induced augmentation of intracellular methotrexate polyglutamate levels is also demonstrated. Apparently, VM-26 and VP-16-213 enhance net cell accumulation of methotrexate and methotrexate polyglutamyl derivatives in the Ehrlich ascites tumor in vitro at concentrations of these agents which are achieved in vivo. Potential therapeutic synergism between methotrexate and epipodophyllotoxins on the basis is therefore possible and is currently under evaluation in animal tumor systems.