Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979.
Overexpression of P-glycoprotein (Pgp) by tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics. MDR cells may be sensitized to these oncolytics when treated with a Pgp modulator. The present study evaluates LY335979 as a modulator both in vitro and in vivo. LY335979 (0.1 microM) fully restored sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol in CEM/VLB100 cells. LY335979 modulated Dox cytotoxicity even when LY335979 (0.5 microM) was removed 24 h prior to the cytotoxicity assay. LY335979 blocked [3H]azidopine photoaffinity labeling of the M(r) approximately 170,000 Pgp in CEM/VLB100 plasma membranes and competitively inhibited equilibrium binding of [3H]vinblastine to Pgp (Ki of approximately 0.06 microM). Treatment of mice bearing P388/ADR murine leukemia cells with LY335979 in combination with Dox or etoposide gave a significant increase in life span with no apparent alteration of pharmacokinetics. LY335979 also enhanced the antitumor activity of Taxol in a MDR human non-small cell lung carcinoma nude mouse xenograft model. Thus, LY335979 is an extremely potent, efficacious modulator that apparently lacks pharmacokinetic interactions with coadministered anticancer drugs and is, therefore, an exciting new agent for clinical evaluation for reversal of Pgp-associated MDR.
Dantzig
A H
AH
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46285-0424, USA.
Shepard
R L
RL
Cao
J
J
Law
K L
KL
Ehlhardt
W J
WJ
Baughman
T M
TM
Bumol
T F
TF
Starling
J J
JJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003986:Dibenzocycloheptenes / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D007941:Leukemia P388 / Q000188:drug therapy* / Q000503:physiopathology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use*; D011485:Protein Binding; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D011804:Quinolines; D014747:Vinblastine; D005047:Etoposide; C095179:zosuquidar trihydrochloride; D017239:Paclitaxel