New potent verapamil derivatives that reverse multidrug resistance in human renal carcinoma cells and in transgenic mice expressing the human MDR1 gene.
Multidrug resistance in human renal cell carcinoma is mainly caused by expression of the MDR1 gene and is characterized by a broad spectrum cross resistance to many natural product chemotherapeutic agents. This resistance can be overcome by applying chemosensitizers which inhibit the function of the MDR1 gene product P-glycoprotein. The development of new reversing agents with fewer side effects and a higher potency in modifying resistance is a high priority of research on drug resistance. We have evaluated four new verapamil derivatives on 21 primary human renal cell carcinomas in vitro, and also tested them in an MDR-transgenic mice model. These mice express the human MDR1 gene in their bone marrow cells and measurement of their white blood counts provides a simple, rapid and reliable system to screen for the potency of MDR-reversing agents in vivo. We demonstrate here that all four drugs are effective in reversing multidrug resistance in primary cultures of human renal cell carcinomas when used in combination with vinblastine chemotherapy, and to a lesser extent with doxorubicin or daunomycin chemotherapy. Our in vivo data indicate that two of these reversing agents display low toxicity at high concentrations and are more effective at low, clinically achievable concentrations, than the other two drugs and R-verapamil. These results make the two new drugs attractive candidates to be taken into clinical trials.
Mickisch
G H
GH
Laboratories of Molecular Biology and Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Merlino
G T
GT
Aiken
P M
PM
Gottesman
M M
MM
Pastan
I
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics; D003630:Daunorubicin / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors; D004351:Drug Resistance / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D005796:Genes / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D014747:Vinblastine / Q000037:antagonists & inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil; D003630:Daunorubicin