MDR1 reversal: criteria for clinical trials designed to overcome the multidrug resistance phenotype.
Multidrug resistance (MDR) is a widely studied mechanism of cellular resistance to structurally unrelated cytotoxic agents. The MDR phenotype is related to the overexpression of the MDR1 gene product, P-glycoprotein (P-gp), a transmembrane drug efflux pump. The capacity to compete with the cytotoxic drug for the active outward transport process, thus inhibiting the activity of the P-gp pump, has been demonstrated for numerous non-cytotoxic compounds, termed MDR modulators. The possibility of modulating the activity of the P-gp pump has initiated numerous clinical trials, using a wide range of chemosensitizers. This article reviews these substances, discusses problems that may arise in connection with the concurrent administration of P-gp modulators and chemotherapeutic agents and provides guidelines for the design of future clinical trials. Furthermore, now data are presented concerning the potential of idarubicin to overcome the MDR phenotype.
Hegewisch-Becker
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Department of Oncology and Hematology, Medical University Clinic, Hamburg, Germany.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002986:Clinical Trials as Topic / Q000592:standards*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D007155:Immunologic Factors / Q000009:adverse effects / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D010641:Phenotype; D012107:Research Design; D013997:Time Factors; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D007155:Immunologic Factors; D015255:Idarubicin