CHEMOPREVENTION OF OVARIAN CANCER IN WOMEN USING FENRETINIDE/ORAL CONTRACEPTIVES

流行病学和实验研究表明，口服避孕药（OCP）以及维甲酸芬维A胺（4-HPR）可以降低卵巢癌的风险，但这些药物的化学预防活性的机制还没有很好的理解。常规和分子流行病学没有将卵巢癌的风险与排卵频率相关联，但OCP的风险降低与周期抑制的比例不成正比，这表明其他机制也可能有助于化学预防。类维生素A增加其他组织中基质细胞TGF β的产生;此外，我们已经证明类维生素A和TGF β诱导卵巢癌细胞系以及新鲜分离的肿瘤细胞的协同死亡。4-在意大利一项大型乳腺癌化学预防试验中，HPR降低了卵巢癌的发病率。BRCA 1或BRCA 2突变和卵巢癌家族史的女性患卵巢癌的风险比一般低风险人群高得多。研究表明，在低风险和高风险女性中，事先使用OCP可降低约50%的卵巢癌风险。最近对灵长类动物的一项研究表明，口服避孕药或孕激素治疗可以增加卵巢表面上皮细胞的凋亡，从而可能减少可能导致癌症的遗传改变发生的机会。TGF β被认为既能抑制卵巢表面上皮细胞的增殖，又能诱导转化细胞的凋亡，从而为消除新出现的恶性细胞克隆提供了一种原始的监视机制。我们推测OCP和维甲酸都增加了卵巢基质细胞TGF β的产生，并诱导上皮细胞凋亡。初步研究表明，光纤光谱学可能能够识别卵巢表面和次表面的癌和癌前病变，从而可能为化学预防试验中的评估提供独特的标记。我们将探讨以下假说：1）4-HPR和OCP诱导卵巢表面上皮细胞凋亡。2)卵巢基质细胞产生的TGF β有助于凋亡，并对正常和转化细胞产生不同的影响。3)OCP和4-HPR对低危和高危卵巢上皮的影响可能不同，这些差异可以通过中间标记物的变化来检测。4)光谱学提供了一种独特的中间标记物，用于检测卵巢上皮细胞的早期发育异常或恶变前变化，以及可靠地识别可能随着化学预防而变化的早期增殖变化和凋亡变化。为了研究这些假设，我们提出了两个随机安慰剂对照的化学预防试验，在低风险（无病史，无已知突变）或高风险（BRCA 1或BRCA 2突变，或家族史）的妇女，光学光谱。这些试点研究应阐明卵巢癌的化学预防机制，确定相关的中间生物标志物，并帮助发展明确的化学预防试验的高风险妇女。

Epidemiologic and experimental studies suggest that oral contraceptives (OCP) as well as the retinoid fenretinide (4-HPR) may reduce the risk of ovarian cancer, but mechanisms underlying the chemopreventive activity of these agents are not well understood. Conventional and molecular epidemiology has not correlated risk of ovarian cancer with frequency of ovulation, but the decreased risk from OCP is not directly proportional to the fraction of cycles suppressed, suggesting that other mechanisms might also contribute to chemoprevention. Retinoids increase the production of TGFbeta by stromal cells in other tissues; further, we have demonstrated that retinoids and TGFbeta induce synergistic death in ovarian cancer cell lines as well as in freshly isolated tumor cells. 4-HPR decreased the incidence of ovarian cancer in a large Italian breast chemoprevention trial. Women with BRCA1 or BRCA2 mutations and a family history of ovarian cancer have a much higher risk of developing ovarian cancer than the general low risk population. Studies have shown that prior OCP use reduces the risk of ovarian cancer in both low and high risk women by about 50%. A recent study in primates indicates that treatment with oral contraceptives or progestins can increase apoptosis in ovarian surface epithelial cells, thus perhaps lessening the chance that a genetic alteration will occur which could lead to cancer. TGFbeta is thought both to suppress the proliferation of ovarian surface epithelial cells and to induce apoptosis in transformed cells, thus providing a primitive surveillance mechanism for eliminating emerging clones of malignant cells. We hypothesize that both OCP and retinoids increase the production of TGFbeta from ovarian stromal cells and induce apoptosis in epithelial cells. Preliminary studies suggest that fiber-optic spectroscopy may be able to identify cancerous and precancerous changes on the ovarian surface and subsurface, and thus may provide a unique marker for assessment in chemoprevention trials. We will explore the hypotheses that: 1) 4-HPR and OCP induce apoptosis in ovarian surface epithelial cells. 2) TGFbeta produced by ovarian stromal cells contributes to apoptosis and differentially affects normal and transformed cells. 3) OCP and 4-HPR may affect low and high risk ovarian epithelium differently; these differences will be detectable through variations in intermediary markers. 4) Spectroscopy provides a unique intermediary marker to detect early dysplastic or pre-malignant changes in ovarian epithelial cells as well as reliably identifying both early proliferative changes and apoptotic changes that may change with chemoprevention. To investigate these hypotheses, we propose two randomized placebo- controlled chemoprevention trials in women at low risk (no history, no known mutations) or at high risk (BRCA1 or BRCA2 mutations, or family history), optical spectroscopy. These pilot studies should elucidate mechanisms of chemoprevention in ovarian cancer, identify relevant intermediate biomarkers, and help in development of definitive chemoprevention trials for high risk women.