Efficient inhibition of intraperitoneal human ovarian cancer growth and prolonged survival by gene transfer of vesicular stomatitis virus matrix protein in nude mice

Abstract

Vesicular stomatitis virus (VSV) matrix protein (MP) has been reported to be capable of inducing apoptosis in vitro in the absence of other viral components. In the present study, the antitumor effect of a recombinant plasmid encoding VSVMP on human ovarian cancer and its apoptosis-inducing efficacy in vivo were further investigated. The recombinant plasmid DNA carrying VSVMP-cDNA (VSVMP-p) was constructed. SKOV3 ovarian cancer cells were transfected with VSVMP-p and examined for apoptosis by Hoechst 33258 staining and flow cytometric analysis. For in vivo study, intraperitoneal ovarian carcinomatosis models in nude mice were established and randomly assigned into four groups to receive six twice-weekly i.p. administrations of VSVMP-p/liposome complexes, empty plasmid/liposome complexes, liposome alone or 0.9% NaCl solution, respectively. The weight of intraperitoneal carcinomatosis and the survival were monitored. Tumor tissues were inspected for apoptosis by TUNEL and Hoechst-33258 assay. Plentiful apoptosis were observed in SKOV3 cells transfected with VSVMP-p. VSVMP-p reduced intraperitoneal tumor weight by about approximately 90% compared with control agents (p<0.01) and significantly prolonged the survival of tumor-bearing mice (p<0.05), with in vivo apoptosis index of 12.6+/-2.7% which was much higher than that of control groups (<4%) (p<0.05). Interestingly, this antitumor effect was accompanied by a noticeable NK cell accumulation. The treatment with VSVMP-p was devoid of any conspicuous toxicity. These observations suggest that VSVMP-p have strong antitumor effects by inducing apoptosis and possibly NK cell-mediated tumor resistance mechanisms, and it may be a potentially effective novel therapy against human ovarian cancer.