Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: Insights of the mechanism of action |
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| Authors: | Samuel Zalipsky Maha Saad Radwan Kiwan Elizabeth Ber Ning Yu Tamara Minko |
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| Affiliation: | 1. ALZA Corporation, Mountain View, CAUSA;2. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJUSA |
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| Abstract: | The antitumor activity of a novel thiolytically cleavable lipid-based prodrug of mitomycin C (MMC) delivered by STEALTH® liposomes (SL) was studied in drug resistant human ovarian carcinoma A2780/AD model and compared with free MMC and both free and SL forms of an established anticancer drug—doxorubicin (DOX). It was found that SL-prodrug (SL-pMMC) possessed enhanced antitumor activity when compared with the parent MMC, free DOX, and SL-DOX. An observance of the high antitumor efficiency of SL-pMMC was a result of its preferential accumulation in the tumor by the enhanced permeability and retention (EPR) effect, suppression of multidrug resistance (MDR) associated with P-glycoprotein and MRP drug efflux pumps, activation of caspase-dependent apoptosis signaling pathways and suppression of antiapoptotic cellular defense by increasing the BAX/BCL2 ratio. Consequently, the described SL-pMMC formulations can be considered good candidates for the chemotherapy of multidrug resistant tumors. |
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| Keywords: | STEALTH® liposome (SL) Liposomal prodrug of Mitomycin C multidrug resistance (MDR) thioredoxin enhanced permeability and retention (EPR) effect apoptosis |
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