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Strategies to Accomplish Targeted Expression of Transgenes in Ovarian Cancer for Molecular Therapeutic Applications¹

Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery [E. C., J. G-N., M. Y., Y. A., C. J. C., W. O. A., S. D. B., M. H. W., P. J. M., A. H., D. T. C.], Departments of Pathology, Cell Biology, and Surgery [G. P. S.], Departments of Obstetrics/Gynecology [M. N. B., T. B. P., R. D. A.], and the Gene Therapy Center [E. C., J. G-N., M. Y., Y. A., C. J. C., W. O. A., S. D. B., M. H. W., P. J. M., A. H., G. P. S., D. T. C.], University of Alabama at Birmingham, Birmingham, Alabama 35294; and Servicio de Oncologia Medica, Hospital La Paz, Madrid, Spain 28046 [E. C., M. G-B.]

Purpose: The purpose of the study was to determine the capability of the midkine (MK) and cycooxygenase-2 (cox-2) gene promoter regions to function as tumor-specific promoters for use in targeted gene therapy of ovarian cancer.

Experimental Design: Established and primary ovarian cancer and mesothelial cells were transduced by adenoviral vectors containing a reporter or thymidine kinase gene expressed under the control of the MK, cox-2, or cytomegalovirus (CMV) promoters. SCID or C57BL/6 mice were injected i.p. with these same vectors. In vitro reporter gene expression and cellular cytotoxicity was determined using luciferase and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. Acute toxicity in vivo was assessed by histological evaluation of harvested tissues.

Results: Consistent activation of the MK and cox-2 promoters was noted in all of the ovarian cancer cell lines in addition to primary ovarian cancer cells. In contrast, reduced reporter activity was reported in mesothelial cells transduced with adenoviruses containing the test promoters, which was especially apparent for the cox-2 promoter. Additionally, the cox-2 promoter exhibited significantly lower reporter gene levels in liver and peritoneum than the control promoter in in vivo experiments. Tumor-cell killing induced by Adcox-2 MTK was comparable to that observed with AdCMVTK. However, a clear differential toxicity pattern was observed in favor of animals treated with Adcox-2 MTK when compared with controls.

Conclusions: These data clearly demonstrate that the transcriptional control afforded by the cox-2 promoter is tumor-specific and is able to mitigate associated toxicity in normal tissue while maintaining therapeutic efficacy in the context of an ovarian cancer molecular chemotherapeutic approach.

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