Retinoids for ovarian cancer prevention: laboratory data set the stage for thoughtful clinical trials.
Retinoids for ovarian cancer prevention: laboratory data set the stage for thoughtful clinical trials.
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用于预防卵巢癌的类维生素A：实验室数据为深思熟虑的临床试验奠定了基础。
DOI：
10.1093/jnci/93.7.486
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Decensi,A
中科院分区：
文献类型：
--
作者：
Veronesi,U;Decensi,A
卵巢癌是一种高度致命的疾病，是西方国家妇女癌症死亡的主要原因之一。由于缺乏有效的筛查和早期诊断方法，目前正在寻求预防，作为降低死亡率的最有希望的方法之一。虽然预防性卵巢切除术越来越多地用于高危妇女，但其短期和长期发病率尚不清楚。更重要的是，大多数卵巢癌都是散发性的，预防性卵巢切除术在平均风险妇女中的广泛使用是不可想象的。一项流行病学研究（1）表明，口服避孕药的使用与一般人群以及BRCA 1杂合子中卵巢癌风险的降低有关。然而，在有乳腺癌家族史的女性中，口服避孕药的使用与该疾病的额外风险相关（2）。因此，正在研究其他药物，这些药物可能取代口服避孕药或与口服避孕药联合使用，以预防卵巢癌。在这些药物中，类维生素A一直是最深入研究其预防癌症潜力的主题（3）。类维生素A对卵巢癌的体内作用的第一个证据来自Formelli和Cleris（4）使用维甲酸类似物芬维A胺（N-4-羟基苯基维A酰胺）进行的研究。类维生素A预防卵巢癌的潜力随后在芬维A胺降低第二次乳腺癌发病率的III期试验中得到证实（5）。在5年的干预期间，与对照组相比，芬维A胺组的卵巢癌发病率在统计学上显著降低（分别为0例和6例）（6）。然而，由于意外的结果和有限的事件数量，观察应极为谨慎。此外，在随后的随访期间，明显的益处部分丧失，这表明芬维A胺的潜在预防作用不持久，治疗必须无限期地继续，以使益处继续（5）。然而，对次要临床试验终点的关注往往会产生新的探索假设。因此，这一发现促使不同的实验室进一步深入了解这一临床发现。自最初的临床观察（6）以来，几项体内和体外研究（4，7-9）一致表明，芬维A胺以及其他天然和合成的维生素A类似物可以在临床相关浓度下有效抑制卵巢癌生长并诱导细胞凋亡。更重要的是，卵巢癌是一种类固醇激素依赖性癌症，在几种情况下倾向于表达高浓度的雌激素受体（ER），特别是在交界性肿瘤和分化良好的浸润性癌症中，可以观察到对他莫昔芬的可测量反应（10，11）。数据（11）还表明卵巢癌组织表达大量的视黄酸受体（RAR）-并且这些水平与ER表达和分化程度高度相关。已知大多数类维生素A，包括芬维A胺，在ER阳性乳腺癌细胞系中发挥更大的抗肿瘤活性。已知芬维A胺通过几种途径抑制致癌作用，其中一种途径涉及与RAR结合，推测是通过抑制视黄酸催化剂（12）。由于RAR-受雌激素受体调节，并受到雌二醇的积极刺激，因此，芬维A胺在绝经前妇女的第二次乳腺癌和卵巢癌中的获益的一种解释可能与通过结合RAR-的生长抑制有关。根据这一概念，我们已经显示出更少的...
Ovarian cancer is a highly lethal disease and represents one of the leading causes of cancer death among women in Western countries. Since effective methods of screening and early diagnosis are lacking, prevention is being sought as one of the most promising ways to reduce mortality. While prophylactic oophorectomy is increasingly used for high-risk women, its short-and long-term morbidity is unknown. More important, most ovarian cancers are sporadic, and the widespread use of prophylactic oophorectomy in average-risk women is unimaginable. An epidemiologic study (1) has shown that oral contraceptive use is associated with reduced ovarian cancer risk among the general population as well as in BRCA1 heterozygotes. In women with a family history of breast cancer, however, oral contraceptive use is associated with additional risk of that disease (2). Thus, other agents are being studied that might replace or be combined with oral contraceptives for prevention of ovarian cancer. Among these agents, retinoids have been the subject of the most intensive investigation of their potential to prevent cancer (3). The first evidence of an in vivo effect by retinoids on ovarian cancer came from the study by Formelli and Cleris (4) using the retinoic acid analogue fenretinide (N-4-hydroxyphenylretinamide). The potential of retinoids for the prevention of ovarian cancer was subsequently confirmed in the phase III trial of fenretinide for the reduction in the incidence of second breast cancer (5). During the 5-year intervention period, a statistically significant lower incidence of ovarian cancer was noted in the fenretinide group compared with the control group (no cases versus six cases, respectively)(6). However, because of the unexpected results and the limited number of events, the observation should be viewed with extreme caution. In addition, the apparent benefit was partially lost during the subsequent followup period, suggesting that the potential preventive effect of fenretinide was not lasting and that treatment would have to be continued indefinitely for the benefit to continue (5). However, attention to secondary clinical trial endpoints often yields new hypotheses for exploration. Thus, the finding prompted different laboratories to provide further insight into this clinical finding. Since that initial clinical observation (6), several in vivo and in vitro studies (4, 7–9) have consistently shown that fenretinide, as well as other natural and synthetic analogues of vitamin A, can effectively inhibit ovarian cancer growth and induce apoptosis at clinically relevant concentrations. More important, ovarian cancer is a steroid hormone-dependent cancer that tends to express high concentrations of estrogen receptors (ERs) in several situations, particularly in borderline tumors and in welldifferentiated invasive cancers, where measurable responses to tamoxifen may be observed (10, 11). Data (11) also indicate that ovarian cancer tissue expresses substantial amounts of retinoic acid receptor (RAR)-and that these levels are highly associated with ER expression and degree of differentiation. Most retinoids, including fenretinide, are known to exert a greater antitumor activity in ER-positive breast cancer cell lines. Fenretinide is known to inhibit carcinogenesis through several pathways, one of which involves binding to RARs, presumably by inhibition of retinoic acid catabolism (12). Since RAR-is under ER regulation and is positively stimulated by estradiol, one explanation for the benefit of fenretinide in second breast and ovarian cancers in premenopausal women may, therefore, be related to the growth inhibition through binding to RAR-. In line with this notion, we have shown fewer …
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路易斯安那州新奥尔良
DOI：
--
发表时间：
--
期刊：
影响因子：
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作者：
James J. Mcloughlin
通讯作者：
James J. Mcloughlin
影响因子：
11.2
作者：
J. Clifford;D. Menter;Michael Wang;R. Lotan;S. Lippman
通讯作者：
J. Clifford;D. Menter;Michael Wang;R. Lotan;S. Lippman
DOI：
10.1007/978-1-59259-423-8_4
发表时间：
2003
期刊：
--
影响因子：
--
作者：
J. Draper;H. Moore;P. Andrews
通讯作者：
J. Draper;H. Moore;P. Andrews
影响因子：
10.3
作者：
Guruswamy, S;Lighfoot, S;Benbrook, DM
通讯作者：
Benbrook, DM
乙酸视黄酯和 4-羟基苯基视黄酰胺对化学诱导的乳腺肿瘤起始的影响。
影响因子：
2
作者：
Grubbs,CJ;Eto,I;Juliana,MM;Hardin,JM;Whitaker,LM
通讯作者：
Whitaker,LM