Mechanism of cross-resistance between vincristine and daunorubicin in Ehrlich ascites tumor cells.

An investigationwas undertakenof the mechanismof a previouslyreportedcross-resistancebetweenvincristine (VCR) and daunorubicin(DNR) in Ehrlichascites tumor cells. No significantdifferencewas demonstratedfor the time course of [3H]VCRuptake in cells resistantto VCR (EHR 2/VCR+) and in cells resistant to DNR (EHR 2/ DNR+), whereaswild-typecellsaccumulatednearly6-fold more drug at steady state. The energy dependence of [3H]VCRand of DNR transportwas investigatedby the metabolic inhibitorssodium azide and iodoacetic acid. These studies revealed that uptake of [3H]VCRand of DNR was depressed in both resistant sublines by an energy-dependent process that mostly requires energy fromglycolysis.If glucosewas omittedfromthe medium together with addition of sodium azide, the uptake of [3H]VCRand of DNR in EHR 2/VCR+ reached a level nearly equal to that of wild-typecells. If glycolysiswas restored by addition of glucose to the resistant cells loaded with drug in this way, a pronouncedextrusionof [3H]VCRand of DNRwas induced.In a similarexperiment with wild-type cells, a slight but significant extrusion of [3H]VCRcouldbe induced. The studiesshowedthat, fornearlyunidirectionalinflux, thecellsmustbe incubatedinthe mediumwithoutglucose butwithsodiumazide. Inthismediumthe influxof [3H]VCR andof DNRwas significantlyhigherinwild-typecellsthan in cells from the resistant sublines. The flux of DNR was notcompetitivelyinhibitedbyVCReither inwild-typecells or in resistantcells.The data indicatethatthe mechanism of cross-resistancebetween VCR and DNR in Ehrlich ascites tumor cells is a result of at beast two different mechanisms: (a) an energy-dependentdrug extrusion commonto VCR and DNR; and (b) unspecificchanges in the membrane, which reduce the influx of both com