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)和维甲酸(4-HPR)可以降低卵巢癌的风险，但这些药物的化学预防作用机制尚不清楚。传统和分子流行病学并未发现卵巢癌的风险与排卵频率相关，但OCP风险的降低与周期被抑制的比例并不成正比，这表明其他机制也可能有助于化学预防。维甲酸增加了其他组织中基质细胞产生的转化生长因子β；此外，我们还证明了维甲酸和转化生长因子β在卵巢癌细胞系中以及在新分离的肿瘤细胞中诱导协同死亡。在意大利的一项大型乳房化学预防试验中，4-HPR降低了卵巢癌的发病率。具有BRCA1或BRCA2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，事先使用口服避孕药可将低风险和高风险女性患卵巢癌的风险降低约50%。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，从而可能降低发生导致癌症的基因改变的可能性。肿瘤生长因子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测机制。我们假设OCP和维甲酸都能增加卵巢基质细胞产生TGFβ，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亚表面的癌和癌前病变，因此可能为化学预防试验中的评估提供一个独特的标记。我们将探讨以下假设：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TGFβ促进细胞凋亡，对正常细胞和转化细胞有不同程度的影响。3)OCP和4-HPR对低危和高危卵巢上皮的影响可能不同，这些差异将通过中间标志物的变化来检测。4)光谱学提供了一种独特的中介标记物来检测卵巢上皮细胞的早期异常增生或癌前病变，并可靠地识别早期增殖性变化和可能通过化学预防而改变的凋亡变化。为了研究这些假说，我们提出了两个随机的安慰剂对照的化学预防试验，在低风险(无病史，没有已知突变)或高风险(BRCA1或BRCA2突变，或家族史)的女性中进行，光学光谱学。这些先导性研究将阐明卵巢癌的化学预防机制，确定相关的中间生物标志物，并帮助开发针对高危女性的明确的化学预防试验。

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.