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Adenoviral-mediated Transfer of a Heat-inducible Double Suicide Gene into Prostate Carcinoma Cells¹

Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan 48073

Tumor cells that express a fusion gene comprised of Escherichia coli cytosine deaminase (CD) and herpes simplex virus type 1 thymidine kinase (TK) sequences exhibit activation of and subsequent killing by the normally innocuous prodrugs 5-fluorocytosine and ganciclovir (Rogulski et al., Hum. Gene Ther., 8: 73–85, 1997). To target localized expression of this therapeutic gene, we have constructed a recombinant adenovirus containing the CD-TK fusion gene under the control of a human inducible heat shock protein 70 promotional sequence. Strong expression of the fusion gene product was induced by heating at 41°C for 1 h. Expression levels obtained were dependent on the multiplicity of infection used and the incubation time after heat shock. Heat-induced expression of the CD-TK protein significantly reduced the survival of PC-3 cells in the presence of both 5-fluorocytosine and ganciclovir. These studies represent a novel form of gene therapy for the transduction and regulation of a double suicide gene in tumor cells and may provide a unique application for hyperthermia in cancer therapy.

¹ Supported by National Cancer Institute Grants CA48000 and CA44550 and William Beaumont Research Institute Grants 97-06 and 97-22M.

² To whom requests for reprints should be addressed, at Radiation Oncology Research Laboratories, William Beaumont Hospital, 3601 West Thirteen Mile Road, Royal Oak, MI 48073-6769. Phone: (248) 551-2568; Fax: (248) 551-2443.

Received 12/ 1/97. Accepted 2/ 5/98.

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