Modulation of mdr1 expression by cytokines in human colon carcinoma cells: an approach for reversal of multidrug resistance.
Reversal of multidrug resistance (MDR) may offer a means of increasing the effectiveness of tumour chemotherapy. A variety of recent evidence indicates that cytokines may be particularly useful in this endeavour. To investigate the molecular mechanism by which cytokines may sensitise multidrug-resistant colon carcinoma cells, HCT15 and HCT116, to treatment with MDR-related drugs, we evaluated the effects of the human cytokines tumour necrosis factor alpha (TNF alpha), interleukin 2 (IL-2) and interferon gamma (IFN gamma) on mdr1 gene expression at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR) and at the protein level with monoclonal antibodies by immuno flow cytometry. P-glycoprotein function was examined after accumulation of the fluorescent drug, doxorubicin, by flow cytometry. Chemosensitivity to doxorubicin and vincristine was analysed using the XTT assay. All three cytokines were found to modulate the MDR characteristics on mdr1 expression levels, P-glycoprotein function and measured chemosensitivity to MDR-associated anti-cancer drugs. This cytokine-induced reversal of MDR was strongly time dependent, with maximal effects after 48 and 72 h of cytokine treatment. If similar modulation of MDR phenotype can be obtained in in vivo models, it may be possible to verify the time course for modulation by cytokine treatment and to design appropriate clinical trials of this strategy for MDR reversal.
Laboratory of Drug Discovery Research and Development, Division of Cancer Treatment, National Cancer Institute, Frederick, Maryland 21702-1201, USA.
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Stein
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Walther
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Shoemaker
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D007376:Interleukin-2; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D007371:Interferon-gamma