Chemoprevention of Ovarian Cancer: Modulation of Biomarkers in Primates Using Fenretinide (4-HPR) and Oral Contraceptives

Principal Investigator: Molly A. Brewer, D.V.M., M.D.

Epidemiologic and experimental studies suggest that oral contraceptives (OCP) and a synthetic form of vitamin A called N-(4-hydroxyphenyl) fenretinide (4-HPR) may reduce the risk of ovarian cancer, but mechanisms of action of these agents remain unknown.

Several studies have correlated the risk of ovarian cancer with frequency of ovulation. OCP suppress ovulation, but the decrease in risk of developing ovarian cancer is not directly proportional to the number of menstrual cycles suppressed. This suggests that other mechanisms might also contribute to the chemopreventive effect.

A recent study in primates indicates that treatment with oral contraceptives or with progestins can increase apoptosis (cell death) in ovarian surface epithelial cells. Apoptosis is considered a defense mechanism of the organism against cancerous cells. Our group has found that transforming growth factor-beta (TGFß) induces apoptosis in abnormal ovarian cells.

Consequently, TGFß may provide a surveillance mechanism for eliminating emerging malignant cells. At the present time, there is not an animal model for ovarian cancer chemoprevention or ovarian cancer and the purpose of this proposal is development of the Rhesus monkey to serve as a model for cancer in humans. One of the advantages of such a closely related animal model will be that testing not possible in humans, can be done in monkeys to learn how drugs prevent ovarian cancer. Understanding how these drugs work will aid both in the understanding of how ovarian cancer can be prevented and gives clues to how it develops. The primate is very close genetically to the human, and is the only mammal that has menstrual cycles like a woman.

These close similarities will allow us to take knowledge learned in monkeys and apply these same principles to women. The purpose of this project is to develop an animal model to test the activity of OCP and 4-HPR in Rhesus monkey ovaries, which will promote further understanding how these drugs prevent cancer and will help us develop better methods to prevent ovarian cancer in women.