The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein.
P-glycoprotein (Pgp)-mediated drug efflux is a major factor contributing to the variance of absorption and distribution of many drugs, particularly cancer chemotherapeutics. Multidrug resistance (MDR) is caused largely by the efflux of therapeutics out of the tumor cell by Pgp, resulting in reduced efficacy of chemotherapy. SCH66336, a farnesyl transferase inhibitor in development for cancer therapy, was examined in the present study for its ability to inhibit Pgp. In a test system consisting of a NIH-G185 cell line presenting an overexpressed amount of the human transporter Pgp, known Pgp inhibitors, such as cyclosporin A, paclitaxel, verapamil, tamoxifen, and vinblastine, were demonstrated to inhibit the Pgp-mediated efflux of daunorubicin. SCH66336 significantly inhibited daunorubicin transport with an IC50 of about 3 microM and similarly affected the transport of rhodamine 123 with a potency similar to cyclosporin A. Additionally, by an ATP-hydrolysis assay, SCH66336 was shown to decrease Pgp-mediated ATP hydrolysis by >70% with a Km of 3 microM. This observation indicates that SCH66336 directly interacts with the substrate binding site of Pgp, a quality unique to SCH66336 and its analogues, although not inherent to farnesyl transferase inhibitors in general. Moreover, low concentrations of SCH66336 exhibit synergy with the Pgp substrate/inhibitors paclitaxel, tamoxifen, and vinblastine respectively by significantly potentiating their inhibition of Pgp. Treatment with SCH66336 would be predicted to be synergistic with coadministered cancer therapeutics that are substrates of Pgp. A further benefit of coadministration of SCH66336 could be reduced chemotherapy dosage, hence, lower exposure to normal cells and, therefore, less undesired toxicity.
Wang
E
E
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, New Jersey 07848, USA.
Casciano
C N
CN
Clement
R P
RP
Johnson
W W
WW
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003630:Daunorubicin / Q000493:pharmacokinetics; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D019450:Genes, MDR; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013629:Tamoxifen / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology; D003986:Dibenzocycloheptenes
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D003630:Daunorubicin; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; D020112:Rhodamine 123; D013629:Tamoxifen; D014747:Vinblastine; C115354:lonafarnib; D003986:Dibenzocycloheptenes