Acquired vs innate multidrug resistance and the effect of calcium channel blockers.
Innate drug resistance as well as acquired multidrug resistance are directly related to ineffectiveness and failure of the cancer chemotherapy. The mechanisms of such resistance, especially those of innate resistance, have not been fully elucidated. We have established vincristine (VCR)- and Adriamycin (ADM)-resistant sublines of human myelogenous leukemia K562 by continuous drug exposure. These resistant sublines contained double minute chromosomes and express a glycoprotein with a 180,000 dalton M.W. Analysis of VCR and ADM sensitivities of several isolated clones from these resistant sublines revealed a tight relationship between these two resistant mechanisms. However, ADM resistant sublines are always highly resistant to VCR, but VCR resistant sublines are not necessarily highly resistant to ADM, suggesting the presence different mechanisms of ADM and VCR resistance. Calcium channel blockers inhibit the drug efflux in these resistant tumor cells, thereby overcoming of drug resistance. Greater potentition was observed with antitumor agents to which VCR- and ADM-resistant cells were highly cross-resistant. Calcium channel blockers always show higher potentiation with VCR than ADM, and the clones with greater resistance to VCR generally accumulated less VCR and generally possessed a higher rate of VCR efflux. These results might indicate that a major mechanism of VCR resistance could be a defficiency in drug transport and this mechanism can be reversed by calcium channel blockers, while the ADM resistance mechanisms are partly related to drug efflux and only this mechanism of the ADM resistance can be modulated by calcium channel blockers. Calcium channel blockers also potentiate the drug effects, especially that of vinca alkaloids, in innately resistant tumors cells, indicating that such innate resistant cells also share a similar resistance mechanism to that observed in acquired drug resistance. From these results, the mechanisms of acquired and innate drug resistance are discussed.
Tsuruo
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D007951:Leukemia, Myeloid / Q000188:drug therapy; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D014751:Vindesine / Q000494:pharmacology
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D006023:Glycoproteins; D014750:Vincristine; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil; D014751:Vindesine