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Prostate-specific Amplification of Expanded Polyglutamine Expression: A Novel Approach for Cancer Gene Therapy¹

The 4th Department, Osaka Bioscience Institute, Suita, Osaka 565-0874 [T. S., H. T., A. K.]; Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8315 [T. S., H. T., S. N.]; and Department of Urology, Kyoto University Faculty of Medicine, Kyoto 606-8397 [T. S., Y. K., O. Y.], Japan

For cancer gene therapy, it is of primary importance to develop a system to sufficiently and selectively express therapeutic genes in cancer cells. In this study, we showed that an approximately 5.3-kb promoter region of the prostate-specific antigen (PSA) gene can replicate the endogenous expression pattern, although its expression is very weak. We then developed a novel two-step transcriptional activation system in which the PSA promoter drives an artificial transcriptional activator, GAL4-VP16 fusion protein, and it in turn activates transgene expressions under the control of GAL4-responsive elements. By using this system, transgene expressions can be greatly augmented while maintaining prostate-specific expression. Finally, we applied this system to drive an expanded polyglutamine, a potent proapoptotic molecule, to induce apoptosis selectively in PSA-positive prostate cancer cells. This novel system would provide an ideal approach for cancer gene therapy applicable not only to prostate cancer but to other cancers as well.

¹ Supported in part by research grants for scientific research on priority areas from the Ministry of Education, Science, Sports and Culture of Japan, by Special Coordination Funds of the Science and Technology Agency of the Japanese government, and by Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation.

² To whom requests for reprints should be addressed, at The 4th Department, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. Phone: 81-6-872-4853; Fax: 81-6-872-3933; E-mail: kakizuka@obi.or.jp.

Received 1/20/98. Accepted 4/17/98.

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