Mutant SV40 large T antigen as a therapeutic agent for HER-2/neu-overexpressing ovarian cancer

Cancer Gene Ther. May-Jun 1996;3(3):168-74.

Abstract

The HER-2/neu gene is frequently amplified and/or its protein product, p185, is overexpressed in a number of human cancers. Overexpression of p185 correlates with poor prognosis and low survival rates in ovarian cancer patients. We previously found that the K1 mutant of SV40 large T antigen inhibits rat neu promoter and suppresses mutation-activated rat neu transformation in mouse fibroblasts. We show here that K1 also inhibits human HER-2/neu promoter in human ovarian cancer cells. To investigate whether K1 can suppress HER-2/neu transformation and thus is a potential therapeutic agent, we used an orthotopic ovarian cancer model in which mice were injected intraperitoneally with HER-2/neu-overexpressing human ovarian cancer cells to induce tumor development. The tumor-bearing mice were then treated with K1-liposome complex weekly. We found that liposome-mediated K1 gene transfer decreased the p185 protein level by K1 expression in these cancer cells and significantly prolonged mice survival; about 40% of these treated mice were alive for more than 1 year without any tumor development. On the other hand, the animals from control groups that did not receive this gene therapy all developed tumors and died within 7 months. The results indicate that liposome-mediated K1 gene transfer is able to suppress tumor development from HER-2/neu-overexpressing ovarian cancer cells in mice.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Viral, Tumor / biosynthesis*
  • DNA Primers
  • Disease-Free Survival
  • Drug Carriers
  • Female
  • Genetic Therapy / methods*
  • Humans
  • Liposomes
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy*
  • Polymerase Chain Reaction
  • Prognosis
  • Promoter Regions, Genetic
  • Rats
  • Receptor, ErbB-2 / biosynthesis*
  • Receptor, ErbB-2 / genetics
  • Recombinant Proteins / biosynthesis
  • Simian virus 40 / immunology*
  • Survival Rate
  • Time Factors
  • Transcription, Genetic
  • Transfection / methods

Substances

  • Antigens, Viral, Tumor
  • DNA Primers
  • Drug Carriers
  • Liposomes
  • Recombinant Proteins
  • Receptor, ErbB-2