INDUCTION OF APOPTOSIS IN BREAST CANCER

Fontana小组鉴定了一种维甲酸6-[3-1-金刚烷基)-4- 羟基苯基]-2-萘甲酸(AHPN) 维甲酸耐药人的G1期停滞和随后的细胞凋亡 维甲酸核受体非依赖的乳腺癌细胞 路径。AHPN诱导乳腺癌细胞凋亡 缺乏功能性P53并对生长抑制有抗性的品系 维甲酸。因此，AHPN类似物缺乏的鉴定 维甲酸的毒副作用，因为它们不能结合 维甲酸受体将提供新的治疗药物 浸润性乳腺癌。乳腺癌中的细胞凋亡计划将 首先进行调查，以确定 AHPN抑制乳腺癌细胞的生长和凋亡，从而 改进的AHPN类似物可以更容易地识别，然后 检查这些类似物调节乳腺癌的能力 生长和凋亡以确定治疗的最佳类似物 并证实AHPN的作用机制。 具体目标四.AHPN的功能不依赖于视黄醇 受体通过一种独特的途径诱导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 Gadd45启动子通过激活反式转录 元素，或~稳定WAF-1，通过AHPN-消息- 响应元件位于其3‘非翻译区。具体目标四. 显示增强疗效的AHPN类似物将被评估为 它们诱导G1期停滞和细胞凋亡的能力，增强WAF-1 表达，下调bclxl的表达，并增强 化疗诱导的细胞凋亡。具体目标四。AHPN 道森实验室的类似物展示了最伟大的 功效(在低于或的浓度下诱导细胞凋亡 与AHPN相似，但缺乏对维甲酸受体的亲和力 因此将减少系统毒性)将评估其 人乳腺器官培养中调控细胞凋亡的能力 癌症。张实验室发现前景看好的维甲酸 将单独或与化疗药物联合进行评估 毒剂或干扰素。具体目标四。最好的三个 将评估AHPN类似物、维甲酸或维甲酸组合 因为它们有能力诱导细胞凋亡并抑制人的生长 SCID小鼠乳腺癌异种移植瘤研究。

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.