RETINOID, INTERFERON AND TAXOL EFFECTS IN BREAST CANCER

申请人的描述（Applicant's Description） 晚期乳腺癌只能通过化疗暂时控制， 其可能继发于肿瘤抗性机制的发展， 如bcl-2过表达。 我们使用了一种临床前的上皮细胞系 模型，以剖析出bcl-2机制的电阻来自原发性 幼鼠肾上皮细胞（BRK），转染基因 编码鼠温度敏感性p53（va 1135）和bcl-2表达 vector. 我们发现p53突变和bcl-2过表达的细胞， 对紫杉醇（TAX）耐药。 为了使这些细胞敏感 对于TAX，我们发现了几种能够克服p53和bcl-2的活性剂 当与包括13-顺式视黄酸的TAX组合时介导的抗性 和α干扰素（CRA/IFN）。 我们发现，CRA/IFN还增强了 TAX对乳腺肿瘤细胞（MCF-7）和前列腺肿瘤细胞（PC-3）的作用， 两者都过表达bcl-2。 此外，我们发现， CRA/IFN对这些细胞系的作用与bcl-2表达的降低相关。 基于这些数据，我们假设调节细胞凋亡的药物可能与细胞凋亡有关。 bcl-2的表达和肿瘤细胞对化疗的敏感性 实验室将转化为改善的临床结果。 为了验证这一 假设，我们完成了一项I期临床试验，使用CRA/IFN和TAX， 晚期恶性肿瘤患者，并计划治疗晚期 CRA/IFN联合TAX II期试验中的乳腺癌 （使用我们的I期试验中确定的剂量）沿着和详细的 临床标本中bcl-2的分析。

DESCRIPTION (Applicant's Description) Advanced breast cancer is only temporarily controlled with chemotherapy, which may be secondary to the development of tumor resistance mechanisms, such as bcl-2 overexpression. We used a pre-clinical epithelial cell line model to dissect out bcl-2 mechanisms of resistance derived from primary baby rat kidney epithelial cells (BRK), which were transfected with genes encoding the murine temperature sensitive p53(va1135) and a bcl-2 expression vector. We found that cells with p53 mutation and overexpression of bcl-2 were resistant to paclitaxel (TAX). In an attempt to sensitize these cells to TAX, we found several active agents capable of overcoming p53 and bcl-2 mediated resistance when combined with TAX including 13-cis retinoic acid and alpha interferon (CRA/IFN). We found that CRA/IFN also enhanced the effect of TAX on breast tumor cells (MCF-7) and prostate tumor cells (PC-3), both of which overexpress bcl-2. Additionally, we found that the effect of CRA/IFN on these cell lines correlated to reduction in expression of bcl-2. Based on these data, we hypothesized that agents that modulate the expression of bcl-2 and sensitize tumor cells to chemotherapy in the laboratory will translate into improved clinical results. To test this hypothesis, we completed a phase I clinical trial using CRA/IFN and TAX in patients with advanced malignancy and plan to treat patients with advanced breast cancer in a phase II trial with CRA/IFN in combination with TAX (using the dose established in our phase I trial) along with and a detailed analysis of bcl-2 in clinical specimens.