CHEMOPREVENTION OF OVARIAN CANCER IN WOMEN USING FENRETINIDE/ORAL CONTRACEPTIVES

使用芬维A胺/口服避孕药化学预防女性卵巢癌

• 批准号: 6357022
• 负责人: ROBERT C BAST
• 金额: $ 19.33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6357022
• 关键词: adult human (21+); apoptosis; biomarker; brca gene; cancer risk; chemoprevention; clinical research; clinical trials; colorimetry; cooperative study; family genetics; fenretinide; fluorescence spectrometry; gene mutation; genetic susceptibility; human subject; human therapy evaluation; in situ hybridization; neoplasm /cancer nutrition therapy; northern blottings; nutrition related tag; oral contraceptives; ovary neoplasms; polymerase chain reaction; statistics /biometry; transforming growth factors; western blottings; women's health

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.

流行病学和实验研究表明，口服避孕药（OCP）以及类维生素类似烯酸（4-HPR）可能会降低卵巢癌的风险，但是这些药物的化学预防活性的基本机制却尚不清楚。常规和分子流行病学与卵巢癌的风险与排卵的频率没有相关性，但是OCP的降低风险与抑制的周期的比例不成比例，这表明其他机制也可能有助于化学预防。类视网膜类似于其他组织中基质细胞的TGFBETA产生。此外，我们已经证明了类视黄素和TGFBETA在卵巢癌细胞系以及新鲜分离的肿瘤细胞中诱导协同死亡。在一项大型意大利乳房化学预防试验中，4-HPR降低了卵巢癌的发病率。患有BRCA1或BRCA2突变以及卵巢癌家族史的女性患卵巢癌的风险要高于一般的低风险人群。研究表明，先前的OCP使用将低风险女性和高风险女性的卵巢癌风险降低了约50％。一项针对灵长类动物的研究表明，口服避孕药或孕激素的治疗​​可以增加卵巢表面上皮细胞中的凋亡，因此也许会减少发生遗传改变可能导致癌症的机会。 TGFBETA既可以抑制卵巢表面上皮细胞的增殖，又诱导转化细胞中的凋亡，从而提供了一种原始的监视机制来消除恶性细胞的新兴克隆。我们假设OCP和类维生素类动物都会增加卵巢基质细胞的TGFBETA产生，并在上皮细胞中诱导凋亡。初步研究表明，纤维光谱可能能够在卵巢表面和地下上识别癌性和癌前变化，因此在化学预防试验中可能为评估提供了独特的标记。我们将探讨：1）4-HPR和OCP在卵巢表面上皮细胞中凋亡。 2）卵巢基质细胞产生的TGFBETA有助于凋亡，并差异地影响正常细胞和转化的细胞。 3）OCP和4-HPR可能对低风险和高风险卵巢上皮有所不同；这些差异将通过中间标记的变化来检测。 4）光谱学提供了独特的中介标记物，可检测卵巢上皮细胞的早期发育不良或预防性变化，并可靠地识别出可能随着化学预防而变化的早期增殖变化和凋亡变化。为了调查这些假设，我们提出了针对低风险的女性（没有病史，没有已知突变）或高风险（BRCA1或BRCA1或BRCA2突变或家族史）的两项随机安慰剂控制的化学预防试验，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，并有助于开发高风险女性的确定化学预防试验。