Clinical studies with modulators of multidrug resistance.
Improved understanding of the mechanisms underlying chemotherapeutic failure has led to new strategies to circumvent drug resistance. Expression of the multidrug transporter, P-glycoprotein (P-gp), is likely to be a significant mechanism contributing to the clinical resistance of some cancers to chemotherapy. Phase I trials of currently available MDR modulators have yielded important pharmacologic principles pertaining to normal tissue P-gp function and its influence on the disposition of MDR-related anticancer drugs. Currently available P-glycoprotein inhibitors lack the potency to completely reverse the MDR phenotype at clinically achievable concentrations. Despite this, encouraging clinical results have been obtained in the hematolymphoid malignancies. As these more potent modulators become available, careful characterization of pharmacologic interactions with MDR-related cytotoxins will be critical to the rational design of Phase II and III studies that will ultimately test the efficacy of MDR modulation.
Fisher
G A
GA
Stanford University School of Medicine, Stanford University Medical Center, California, USA.
Sikic
B I
BI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003524:Cyclosporins / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012107:Research Design; D016896:Treatment Outcome; D014748:Vinca Alkaloids / Q000494:pharmacology / Q000627:therapeutic use
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D009363:Neoplasm Proteins; D014748:Vinca Alkaloids