MUTANT SV40 LARGE T-ANTIGEN AS A THERAPEUTIC AGENT FOR HER-2 NEU-OVEREXPRESSING OVARIAN-CANCER/

The HER-2/neu gene is frequently amplified and/or its protein product, p185, is overexpressed in a number of human cancers. Overexpression o f p185 correlates with poor prognosis and low survival rates in ovaria n cancer patients. We previously found that the K1 mutant of SV40 larg e T antigen inhibits rat neu promoter and suppresses mutation-activate d rat neu transformation in mouse fibroblasts. We show here that K1 al so 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 cance r model in which mice were injected intraperitoneally with HER-2/neu-o verexpressing human ovarian cancer cells to induce tumor development. The tumor-bearing mice were then treated with K1-liposome complex week ly. we found that liposome-mediated K1 gene transfer decreased the p18 5 protein level by K1 expression in these cancer cells and significant ly 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 thera py all developed tumors and died within 7 months. The results indicate that liposome-mediated K1 gene transfer is able to suppress tumor dev elopment form HER-2/neu-overexpressing ovarian cancer cells in mice.