Journal
JOURNAL OF DRUG TARGETING
Volume 15, Issue 7-8, Pages 518-530Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/10611860701499946
Keywords
STEALTH (R) liposome (SL); liposomal prodrug of mitomycin C; multidrug resistance (MDR); thioredoxin; enhanced permeability and retention (EPR) effect; apoptosis
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Funding
- NATIONAL CANCER INSTITUTE [R01CA111766] Funding Source: NIH RePORTER
- NCI NIH HHS [CA 111766] Funding Source: Medline
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The antitumor activity of a novel thiolytically cleavable lipid-based prodrug of mitomycin C (MMC) delivered by STEALTH((R)) 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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