SEQUENTIAL DOXORUBICIN AND VINORELBINE IN BREAST CANCER

描述(摘自《研究人员摘要》)：这项拟议的研究旨在提供临床和药效学数据，以确定DNA损伤剂(阿霉素)和长春花碱(长春瑞滨)顺序给药治疗乳腺癌的有效性和安全性。这项研究的理论基础是基于以下实验室调查。P53的功能状态影响细胞对各种损伤的反应。野生型p53倾向于生长停滞或细胞程序性死亡(细胞凋亡)，而突变型p53倾向于持续的细胞周期进展。最近的研究表明，P53可能通过对微管相关蛋白4(MAP4)的转录调控来影响肿瘤化疗药物的敏感性。MAP4是一种微管相关蛋白，调节微管的聚合状态。我们的临床前研究表明，DNA损伤后野生型p53的诱导抑制了MAP4，减少了微管的聚合，并增加了对长春花碱的敏感性。因此，这项建议的总体目标是确定这些观察结果是否适用于患者，从而为联合化疗的最佳排序和选择提供理论基础。有II期数据支持同时使用阿霉素和长春瑞滨。这项拟议研究的具体目的是：(1)评估顺序使用破坏DNA的药物(阿霉素)和长春花碱(长春瑞滨)治疗乳腺癌的安全性和有效性。(2)评价乳腺癌患者应用阿霉素和长春瑞滨的药效学反应的可行性：通过检测肿瘤活检组织和外周血单个核细胞中P53和MAP4的蛋白表达，确定DNA损伤剂阿霉素对P53和MAP4表达的影响。

DESCRIPTION (As Adapted from the Investigator's Abstract): The proposed investigation is designed to provide clinical and pharmacodynamic data to determine the efficacy and safety of the sequential administration of a DNA damaging agent (doxorubicin) followed by a vinca alkaloid (vinorelbine) in the treatment of breast cancer. The rationale for this study is based on the following laboratory investigations. The functional status of p53 affects the cellular response to a variety of injuries. Whereas wild-type p53 favors growth arrest or programmed cell death (apoptosis), mutant p53 favors continued cell-cycle progression. Recent studies indicate that p53 may affect the sensitivity to cancer chemotherapeutic drugs through the transcriptional regulation of Microtubule Associated Protein 4 (MAP4), a microtubule associated protein that regulates the polymerization state of microtubules. Our preclinical studies demonstrated that induction of wild-type p53 following DNA damage repressed MAP4, decreased polymerization of microtubules, and increased sensitivity to vinca alkaloids. Therefore, the overall goal of this proposal is to determine if these observations apply to patients, and thereby provide a rationale for optimal sequencing and selection of combination chemotherapy. There are phase II data supporting the concurrent use of doxorubicin and vinorelbine. The specific aims of the proposed investigation are (1) To assess the safety and efficacy of the sequential use of a DNA damaging drug (doxorubicin) followed by a vinca alkaloid (vinorelbine) in the treatment of breast cancer. (2) To assess the feasibility of measuring the pharmacodynamic response to doxorubicin and vinorelbine administered in patients with breast cancer as follows: to determine the effect of DNA damaging agent, doxorubicin, on p53 and MAP4 expression by assaying the proteins in sequential tumor biopsies and peripheral blood mononuclear cells.