Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: insights of the mechanism of action.
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.
Zalipsky
Samuel
S
ALZA Corporation, Mountain View, CA, USA. szalipsky@intradigm.com
Saad
Maha
M
Kiwan
Radwan
R
Ber
Elizabeth
E
Yu
Ning
N
Minko
Tamara
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010539:Permeability; D011355:Prodrugs; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D011355:Prodrugs; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D016685:Mitomycin; D004317:Doxorubicin; D020169:Caspases