BREAST CANCER CHEMOPREVENTION --SYNTHETIC RETINOID HPR

乳腺癌化学预防——合成维甲酸 HPR

• 批准号: 3548564
• 负责人: UMBERTO VERONESI
• 金额: $ 48.27万
• 依托单位: NATIONAL INST FOR THE STUDY CARE TUMORS
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-09-30 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3548564
• 关键词: biopsy; breast neoplasms; cancer prevention; chemoprevention; clinical trials; cooperative study; dosage; drug metabolism; drug screening /evaluation; female; histopathology; human subject; longitudinal human study; mammography; pharmacokinetics; retinoids

The main aim of this study is to evaluate the effectiveness of the synthetic retinoid 4-HPR (N-(4-hydroxyphenyl)retinamide) in preventing breast cancer. 4-HPR (fenretinide) was synthetized at the Johnson & Johnson Laboratories in the late Sixties and subsequently proven to be effective in inhibiting chemically induced mammary carcinomas in different experimental animals. Fenretinide has been shown to have an antiproliferative effect on rat mammary epithelium and to synergistically enhance the inhibition of carcinogenesis resulting from ovariectomy and tamoxifen. Additionally, 4-HPR resulted in toxicity studies in rats to be less toxic than retinyl esters and retinoic acid; it is neither mutagenic nor carcinogenic when given in mice at doses below one hundred times the dosage proposed for humans. Due to its peculiar concentration in the mammary gland and fat (also demonstrated in humans), 4-HPR is here proposed as the agent of choice for a breast cancer chemoprevention study. The design of the study is to orally administer for five years 200 mg daily of 4-HPR (with a three-day drug holiday at the end of each month) to stage I-II breast cancer patients between 33-68 years of age. This intervention schedule is to be randomly assigned versus no treatment in a population of 3,500-5,000 subjects, depending on the biological activity of the retinoid. The principal endpoint of the study is the possible decrease of incidence of new primaries in the contralateral breast. Local, regional and distant recurrences of the disease as well as new primaries in organs other than the breast will also be recorded and analyzed. No placebo is foreseen for the control arm as extensive data are already available on both acute and chronic toxicity of fenretinide: moreover, ethical considerations, too, do not recommend it due to the length of the trial. However, the protocol foresees a blind, unbiased review of all mammograms; cy- tological and histological examinations of all biopsied lumps are also performed by pathologists who do not know the patients who are being treated and those who are not. 1.160 in the 4-HPR arm and 1,148 in the control arm. At the same date, more than 50 patients had already completed the five-year intervention. Funding is requested to complete accrual and to continue the follow-up.

本研究的主要目的是评估 合成类维生素A 4-HPR（N-（4-羟基苯基）维A酰胺）预防 乳腺癌 4-HPR（芬维A胺）在约翰逊& 六十年代末的约翰逊实验室，随后被证明是 有效抑制化学诱导的乳腺癌， 实验动物 芬维A胺已被证明具有 对大鼠乳腺上皮细胞的抗增殖作用， 增强对由卵巢切除术引起的致癌作用的抑制， 他莫昔芬。 此外，4-HPR导致大鼠毒性研究， 毒性低于视黄酯和视黄酸;它既不是诱变剂 也不会致癌，当剂量低于100倍时， 建议用于人类的剂量。 由于其在水中的特殊浓度， 乳腺和脂肪（也在人类中得到证实），这里提出了4-HPR 作为乳腺癌化学预防研究的首选药物。 本研究的设计是口服给药5年，每日200 mg 4-HPR（每个月底有三天的休药期）， 年龄在33-68岁之间的I-II型乳腺癌患者。 这种干预 在以下人群中随机分配治疗方案， 3，500 - 5，000名受试者，取决于类维生素A的生物活性。 本研究的主要终点是发生率可能降低 在对侧乳房中发现了新的初级乳腺。 本地、区域和远程 疾病的复发以及器官中的新原发灶， 乳房也将被记录和分析。 预计无安慰剂用于 对照组，因为已经有大量关于急性和 芬维A胺的慢性毒性：此外，伦理方面的考虑，也做 由于审判时间过长，我不建议这样做。 然而，该协议 预见了对所有乳房X光检查的盲目、公正的审查;细胞学和 所有活检肿块的组织学检查也由 不认识正在接受治疗的患者的病理学家， 谁不是。 4-HPR组为1.160，对照组为1，148。 50多名患者已经完成了为期五年的干预。 要求提供资金，以完成应计项目并继续开展后续行动。