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Liposome-mediated in Vivo Gene Transfer of Antisense K-ras Construct Inhibits Pancreatic Tumor Dissemination in the Murine Peritoneal Cavity¹

Genetics Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan

K-ras point mutation occurs at a characteristically high incidence in human pancreatic cancer. Plasmids expressing antisense (AS), AS-K-ras-LNSX or sense K-ras gene fragment, were first transduced into three human pancreatic cancer cell lines (AsPC-1, MIAPaCa-2, and BxPC-3) by liposome-mediated transfection. A stable expression of antisense or sense K-ras RNA was detected by Northern blot analysis, and Western blot analysis confirmed a reduction of up to 20% of K-ras-specific p21 protein in AsPC-1 cells transduced with AS-K-ras-LNSX. The growth of pancreatic cancer cells with K-ras point mutations (AsPC-1 and MIAPaCa-2) was significantly suppressed after transduction of AS-K-ras-LNSX, although the effect of antisense construct was not found in cells with a wild-type K-ras gene (BxPC-3). Next, to test the efficacy in vivo, AsPC-1 cells were inoculated into the intraperitoneal cavity of nude mice, and 3 days later, the AS-K-ras-LNSX:liposome complex was injected i.p. 3 times. Twenty-eight days after tumor cell inoculation, 9 of 10 control mice developed peritoneal dissemination and/or solid tumors on the pancreas, whereas only 2 of 12 mice treated with AS-K-ras-LNSX showed any evidence of tumors. Although PCR analysis indicated that the injected DNA was delivered to various organs except for the brain, treatment-related toxicity was not observed. This study shows that the liposome-mediated in vivo gene transfer of antisense K-ras construct may be a useful therapeutic strategy for pancreatic cancer.

¹ This work was supported in part by a grant-in-aid for the 2nd Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan, by grants-in-aid for Cancer Research from the Health and Welfare Ministry of Japan, the Ministry of Education, Science and Culture of Japan, and by the Bristol-Myers Squibb Foundation.

² To whom requests for reprints should be addressed.

Received 2/21/95. Accepted 6/26/95.

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