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| Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979 |
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| Author(s): Dantzig AH, Shepard RL, Cao J, Law KL, Ehlhardt WJ, Baughman TM, Bumol TF, Starling JJ |
| Source: CANCER RESEARCH Volume: 56 Issue: 18 Pages: 4171-4179 Published: SEP 15 1996 |
| Times Cited: 195 References: 39 |
| Abstract: 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 mu M) fully restored sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol in CEM/VLB(100) cells. LY335979 modulated Dox cytotoxicity even when LY335979 (0.5 mu M) was removed 24 h prior to the cytotoxicity assay, LY335979 blocked [H-3]azidopine photoaffinity labeling of the M(r) similar to 170,000 Pgp in CEM/VLB(100) plasma membranes and competitively inhibited equilibrium binding of [H-3]vinblastine to Pgp (K-i of similar to 0.06 mu M). 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Dantzig, AH (reprint author), ELI LILLY & CO, LILLY CORP CTR, LILLY RES LABS, INDIANAPOLIS, IN 46285 USA |
| Publisher: AMER ASSOC CANCER RESEARCH, PUBLIC LEDGER BLDG, SUITE 816, 150 S. INDEPENDENCE MALL W., PHILADELPHIA, PA 19106 |
| Subject Category: Oncology |
| IDS Number: VG370 |
| ISSN: 0008-5472 |
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