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Biomarker Modulation in a Nonhuman Rhesus Primate Model for Ovarian Cancer Chemoprevention¹

Departments of Gynecologic Oncology [M. B., D. G., J. T. W., M. F.], Veterinary Sciences Science Park [W. S., L. H.], and Medicine [R. B.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Obstetrics, Gynecology and Reproductive Science, University of Texas Medical School, Houston, Texas 77030 [M. B., M. F.]; and Biomedical Engineering Program, University of Texas at Austin, Austin, Texas 78712 [U. U., R. R-K.]

Objective: The objective of this study was to explore whether a nonhuman primate model could be developed to test drugs for the prevention of ovarian cancer.

Methods: Nineteen adult female Rhesus macaques were given fenretinide (4HPR), oral contraceptives (OCP), the combination (4HPR + OCP), or no medication for 3 months. Exploratory laparotomy was done pre- and postdrug to assess intermediary biomarkers of neoplastic phenotype, proliferation, response pathways, and growth-regulatory and metabolic markers. Fluorescence emission spectra were plotted for each group pre- and postdrug and means were overlaid on these plots and normalized. Fluorescence intensities were compared using the 2-tailed Student t test, (P = 0.1–0.01).

Results: All monkeys tolerated drugs and surgeries without difficulty. Histochemical markers showed no significant trend. However, fluorescence spectroscopy showed increased intensity at 450 nm excitation, 550 nm emission correlating with increased FAD presence. The 4HPR group (P = 0.01) showed higher intensity than the OCP group (P = 0.05–0.07) when compared with the controls. Decreased emission was seen at 350 nm excitation, 450 nm emission correlating with decreased NAD(P)H presence. The OCP group showed the largest change (P < 0.01), and the control group showed the smallest change.

Conclusions: The nonhuman primate is an excellent model to test drug effect on the ovarian surface epithelium and merits additional study. Fluorescence spectroscopy was the most sensitive marker for drug activity and the apparent increase in NAD and FAD in the 4HPR group is consistent with the effect of 4HPR observed in cell culture. The differences between the OCP and the 4HPR groups suggest a different mechanism of activity of these drugs.

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				M. A. Brewer, K. Johnson, M. Follen, D. Gershenson, and R. Bast Jr. Prevention of Ovarian Cancer: Intraepithelial Neoplasia Clin. Cancer Res., January 1, 2003; 9(1): 20 - 30. [Abstract] [Full Text] [PDF]