Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer

Tsunemitsu, Y; Kagawa, S; Tokunaga, N; Otani, S; Umeoka, T; Roth, J A; Fang, B; Tanaka, N
April 2004
Gut;Apr2004, Vol. 53 Issue 4, p554
Academic Journal
Background: Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for various cancers. We recently developed a binary adenoviral vector system that can express the strong proapoptotic gene Box (Ad/PGK-GV1 6-t-Ad/GT-Bax: Ad/Box). Aims: To evaluate the potential of Box gene therapy for gastric cancer, we assessed its antitumour effect in comparison with that of p.53. Methods: The human gastric cancer cell lines MKN- 1, MKN-7, MKN-28, and MKN-45 were treated with Ad/Bax or Ad/p53, and cell viability, transgene expression, and caspase activation were assessed in vitro. To compare the antitumour effects of Ad/Box and Ad/p53 treatment in vivo, subcutaneous tumours and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each mouse underwent intratumoral or intraperitoneal administration of viruses and the growth of implanted tumours was observed after treatment. Results: Treatment with Ad/Box and Ad/p53 resulted in marked Box and p53 protein expression and effective apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN-45 cells showed resistance to Ad/p53 and only treatment with Ad/Box resulted in activation of caspase 3 expression and massive apoptosis. Ad/Sax treatment was more effective in suppressing both subcutaneous and peritoneally disseminated MKN-45 tumours compared with Ad/p53 treatment. Conclusion: Ad/Box treatment significantly inhibited the growth of even p53 resistant gastric cancer in vitro and in vivo. Therefore, adenovirus mediated Box gene transfer may be useful in gene therapy for gastric cancers.


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