INDUCTION OF APOPTOSIS IN BREAST CANCER

乳腺癌中细胞凋亡的诱导

• 批准号: 6102601
• 负责人: JOSEPH A FONTANA
• 金额: $ 25.62万
• 依托单位: MOLECULAR MEDICINE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102601
• 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组已经确定了类维生素类似于6- [3-1-辅助）-4-- 羟基苯基] -2-2-萘和羧酸（AHPN），诱导 G1逮捕和随后的类维生素性抗性人的凋亡 类维生素类核受体独立于乳腺癌细胞 路径。 此外，AHPN诱导乳腺癌细胞凋亡 缺乏功能性p53且对生长抑制具有抵抗力的线 视网膜类似。 因此，识别缺乏AHPN的类似物 类视网膜类似的有毒副作用，因为它们无法结合 到类视黄素受体将为反对的新治疗剂提供 侵入性乳腺癌。 乳腺癌的项目凋亡将 首先进行调查以定义该机制 AHPN抑制乳腺癌细胞中的生长和凋亡，因此 可以更容易地确定改进AHPN的类似物，然后 检查这些类似物调节乳腺癌的能力 生长和凋亡以识别治疗的最佳类似物 乳腺癌并证实AHPN作用的机制。 特定目标IV.1。 AHPN独立于类维生素 通过独特的受体诱导G1停滞和凋亡 机制。 将进行研究以确定是否 机理是（a）与细胞内受体的结合（b）增强 GADD 45启动子通过激活的转录 元素或〜稳定WAF-1，通过AHPN传达信息 其3'untranslated区域中的响应元素。 特定目标IV.2。 将评估显示增强功效的AHPN类似物 它们诱导G1停滞和凋亡的能力增强了WAF-1 表达，下调BCL-XL表达并增强 化学疗法诱导的凋亡。 特定目标IV.3。 AHPN 来自道森实验室的类似物显示出最大的 功效（在低于OR的浓度下诱导凋亡 与AHPN相媲美，但对类视视感受体缺乏亲和力和 因此，将评估其全身毒性的降低） 能够调节人乳房器官培养的细胞凋亡 癌。 张实验室中确定的有前途的类维生素类似 将单独评估或与化学治疗结合进行评估 代理或干扰素。 特定目标IV.4。 最佳三 将评估AHPN类似物，类视黄素或视网膜类似组合 因为它们能够诱导凋亡并抑制人的生长 SCID小鼠的乳腺癌异种移植物。