INDUCTION OF APOPTOSIS IN BREAST CANCER

乳腺癌中细胞凋亡的诱导

• 批准号: 6237121
• 负责人: JOSEPH A FONTANA
• 金额: $ 30.06万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-07 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237121
• 关键词: SCID mouse; apoptosis; breast neoplasms; genetic transcription; neoplasm /cancer nutrition therapy; neoplasm /cancer transplantation; pharmacokinetics; receptor binding; retinoids; tissue /cell culture; vitamin analog; vitamin receptor; vitamin therapy

The Fontana group has identified a retinoid 6-[3-1-adamantyl)-4- hydroxyphenyl]-2-naphthalene-carboxylic acid (AHPN) that induces G1 arrest and subsequent apoptosis in retinoid-resistant human breast carcinoma cells by a retinoid nuclear receptor-independent pathway. Moreover AHPN induced apoptosis in breast cancer cell lines lacking a functional p53 and resistant to growth inhibition of retinoids. Therefore, identification of analogs of AHPN that lack the toxic side effects of retinoids because of their inability to bind to retinoid receptors would offer new therapeutic agents against invasive breast cancer. Project Apoptosis in Breast Cancer will first conduct an investigation to define the mechanism by which AHPN inhibits growth and apoptosis in breast cancer cells, so that improved analogs of AHPN can be more readily identified, then examine the ability of these analogs to modulate breast cancer growth and apoptosis to identify the optimum analogs for treatment of breast cancer and substantiate the mechanism of AHPN action. Specific Aim IV.1. AHPN functions independently of the retinoid receptors to induce G1 arrest and apoptosis through a unique mechanism. Studies will be conducted to determine if this mechanism is (A) binding to an intracellular receptor (B) enhancing gadd 45 promoter transcription through the activation of a trans element, or ~ stabilizing WAF-1 , message through an AHPN- responsive element in its 3'untranslated region. Specific Aim IV.2. AHPN analogs that display enhanced efficacy will be evaluated for their ability to induce G1 arrest and apoptosis, enhance WAF-1 expression, downregulate bcl-XL expression, and enhance chemotherapy-induced apoptosis. Specific Aim IV.3. The AHPN analogs from the Dawson laboratory that display the greatest efficacy (induce apoptosis at concentrations lower than or comparable to AHPN but lack affinity for the retinoid receptors and so will have reduced systemic toxicity) will be assessed for their ability to modulate apoptosis in organ culture of human breast carcinomas. Promising retinoids identified in the Zhang laboratory will be evaluated alone or in combination with chemotherapeutic agents or interferon. Specific Aim IV.4. The optimum three AHPN analogs, retinoids, or retinoid combinations will be assessed for their ability to induce apoptosis and inhibit the growth of human breast carcinoma xenografts in SCID mice.

Fontana 小组已鉴定出类视黄醇 6-[3-1-金刚烷基)-4- 羟基苯基]-2-萘甲酸（AHPN），诱导 类视黄醇耐药人的 G1 期停滞和随后的细胞凋亡 乳腺癌细胞通过类维生素A核受体独立 途径。 此外，AHPN 诱导乳腺癌细胞凋亡 缺乏功能性 p53 且对生长抑制具有抗性的品系 类维生素A。 因此，鉴定缺乏的 AHPN 类似物 类视黄醇由于无法结合而产生毒副作用 视黄醇受体将提供新的治疗药物 浸润性乳腺癌。 乳腺癌细胞凋亡项目将 首先进行调查以确定机制 AHPN 抑制乳腺癌细胞的生长和凋亡，因此 可以更容易地识别 AHPN 的改进类似物，然后 检查这些类似物调节乳腺癌的能力 生长和凋亡以确定最佳治疗类似物 乳腺癌的发生并证实了 AHPN 的作用机制。 具体目标 IV.1。 AHPN 的功能独立于类维生素A 受体通过独特的机制诱导 G1 期停滞和细胞凋亡 机制。 将进行研究以确定这是否 机制是 (A) 与细胞内受体结合 (B) 增强 gadd 45 启动子通过激活反式转录 元素，或者 ~ 稳定 WAF-1 ，通过 AHPN 的消息- 其 3'非翻译区的响应元件。 具体目标 IV.2。 将评估表现出增强功效的 AHPN 类似物 它们诱导 G1 期停滞和细胞凋亡的能力，增强 WAF-1 表达，下调 bcl-XL 表达，并增强 化疗诱导的细胞凋亡。 具体目标 IV.3。 澳大利亚HPN 来自道森实验室的类似物显示出最大的 功效（在浓度低于或 与 AHPN 相当，但缺乏对类视黄醇受体的亲和力 因此将降低系统毒性）将对其进行评估 调节人乳腺器官培养细胞凋亡的能力 癌。 张实验室鉴定出有前景的类维生素A 将单独或与化疗联合评估 剂或干扰素。 具体目标 IV.4。 最优三 将评估 AHPN 类似物、类维生素A 或类维生素A 组合 因其具有诱导细胞凋亡和抑制人类生长的能力 SCID 小鼠乳腺癌异种移植物。