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Modeling Chemotherapy Resistant Leukemia In Vitro
08:41

Modeling Chemotherapy Resistant Leukemia In Vitro

Published on: February 9, 2016

Atypical multiple drug resistance in a human leukemic cell line selected for resistance to teniposide (VM-26)

M K Danks, J C Yalowich, W T Beck

    Cancer Research
    |March 1, 1987
    PubMed

    Insights

    This study characterizes a unique drug-resistant leukemia cell line (CEM/VM-1) that resists etoposide but remains sensitive to Vinca alkaloids. This atypical multidrug resistance involves altered drug-target interaction, not reduced drug concentration.

    Area of Science:

    • * Molecular Pharmacology
    • * Cancer Cell Biology
    • * Drug Resistance Mechanisms

    Background:

    • * Acquired resistance to cytotoxic drugs is a major challenge in cancer chemotherapy.
    • * The
    • classic
    • multidrug resistance (MDR) phenotype typically involves cross-resistance to Vinca alkaloids, anthracyclines, epipodophyllotoxins, and antibiotics.
    • * Understanding novel resistance mechanisms is crucial for developing effective cancer treatments.

    Purpose of the Study:

    • * To characterize a human leukemic cell line (CEM/VM-1) exhibiting an
    • atypical
    • multidrug resistance profile.
    • * To investigate the cellular pharmacology of etoposide in drug-sensitive versus resistant cell lines.
    • * To elucidate the mechanism underlying resistance to epipodophyllotoxins in the CEM/VM-1 cell line.

    Main Methods:

    • * Characterization of drug sensitivity and cross-resistance profiles in the CEM/VM-1 cell line.
    • * Cellular pharmacology studies of [3H]etoposide (VP-16) in CEM/VM-1 and drug-sensitive CEM cells, assessing binding, influx, efflux, and steady-state concentrations.
    • * Comparison of drug-target interaction mechanisms between classic and atypical MDR phenotypes.

    Main Results:

    • * CEM/VM-1 cells exhibit resistance to etoposide, anthracyclines, mitoxantrone, and mAMSA but retain sensitivity to Vinca alkaloids.
    • * Despite a ~40-fold resistance to etoposide's cytotoxic effects, CEM/VM-1 cells show similar cellular pharmacology for [3H]VP-16 compared to sensitive CEM cells.
    • * The resistance mechanism in CEM/VM-1 cells appears unrelated to decreased intracellular drug accumulation.

    Conclusions:

    • * The CEM/VM-1 cell line represents a novel model for studying
    • atypical
    • multidrug resistance.
    • * Resistance to epipodophyllotoxins in this cell line likely stems from an altered interaction between the drug and its cellular target(s).
    • * These findings highlight the diversity of MDR mechanisms and suggest potential therapeutic strategies targeting specific resistance pathways.

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