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Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979
A H Dantzig1, R L Shepard, J Cao
1Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46285-0424, USA.
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 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.
Insights
LY335979 effectively reverses multidrug resistance (MDR) by modulating P-glycoprotein (Pgp). This compound restores cancer cell sensitivity to various chemotherapy drugs and shows promise in preclinical models for enhancing antitumor activity.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Tumor P-glycoprotein (Pgp) overexpression causes multidrug resistance (MDR) to diverse chemotherapeutics.
- Modulators of Pgp can potentially resensitize MDR tumors to standard oncolytics.
Purpose of the Study:
- To evaluate the Pgp modulator LY335979 for its efficacy in reversing Pgp-associated MDR both in vitro and in vivo.
- To assess LY335979's impact on the sensitivity of MDR cancer cells to various anticancer drugs.
Main Methods:
- In vitro assays using CEM/VLB100 cells to assess restored sensitivity to vinblastine, doxorubicin, etoposide, and Taxol.
- In vivo studies in mice bearing P388/ADR leukemia and human non-small cell lung carcinoma xenografts.
- Biochemical assays including photoaffinity labeling and competitive binding to evaluate Pgp interaction.
Main Results:
- LY335979 fully restored sensitivity to multiple oncolytics in MDR cells, with sustained effects even after drug removal.
- The compound demonstrated competitive inhibition of [3H]vinblastine binding to Pgp and blocked photoaffinity labeling.
- In vivo, LY335979 significantly increased lifespan in leukemia models and enhanced Taxol's antitumor activity in lung cancer xenografts without altering pharmacokinetics.
Conclusions:
- LY335979 is a highly potent and effective Pgp modulator with significant preclinical efficacy.
- It shows potential for clinical evaluation in reversing Pgp-mediated MDR due to its efficacy and lack of pharmacokinetic interactions.