Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: insights of the mechanism of action

J Drug Target. Aug-Sep 2007;15(7-8):518-30. doi: 10.1080/10611860701499946.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Caspases / metabolism
  • Disease Models, Animal
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Liposomes
  • Mice
  • Mice, Nude
  • Mitomycin / administration & dosage
  • Mitomycin / pharmacokinetics
  • Mitomycin / pharmacology*
  • Ovarian Neoplasms / drug therapy*
  • Permeability
  • Prodrugs
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • bcl-2-Associated X Protein / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Liposomes
  • Prodrugs
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Mitomycin
  • Doxorubicin
  • Caspases