SEQUENTIAL DOXORUBICIN AND VINORELBINE IN BREAST CANCER

序贯阿霉素和长春瑞滨治疗乳腺癌

• 批准号: 6174003
• 负责人: DEBORAH L TOPPMEYER
• 金额: $ 7.85万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-14 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174003
• 关键词: DNA damage; breast neoplasms; clinical research; combination chemotherapy; doxorubicin; drug screening /evaluation; female; human subject; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; p53 gene /protein; pharmacokinetics; vinca alkaloids; women's health

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.

描述（改编自研究者摘要）：拟定研究旨在提供临床和药效学数据，以确定DNA损伤剂（阿霉素）序贯给药后使用长春花生物碱（长春瑞滨）治疗乳腺癌的疗效和安全性。本研究的依据基于以下实验室研究。p53的功能状态影响细胞对各种损伤的反应。而野生型p53有利于生长停滞或程序性细胞死亡（凋亡），突变型p53有利于细胞周期的持续进展。最近的研究表明，p53可能通过转录调节微管相关蛋白4（MAP 4），一种调节微管聚合状态的微管相关蛋白，影响癌症化疗药物的敏感性。我们的临床前研究表明，诱导野生型p53 DNA损伤后抑制MAP4，减少微管聚合，并增加敏感性长春花生物碱。因此，本提案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依据。有II期数据支持同时使用阿霉素和长春瑞滨。拟定研究的具体目的是（1）评估序贯使用DNA损伤药物（多柔比星）和长春花生物碱（长春瑞滨）治疗乳腺癌的安全性和有效性。(2)评估测量乳腺癌患者对阿霉素和长春瑞滨的药效学反应的可行性，如下：通过测定连续肿瘤活检和外周血单核细胞中的蛋白质，确定DNA损伤剂阿霉素对p53和MAP 4表达的影响。

项目成果

A Phase I/pilot study of sequential doxorubicin/vinorelbine: effects on p53 and microtubule-associated protein 4.

顺序阿霉素/长春瑞滨的 I 期/试点研究：对 p53 和微管相关蛋白 4 的影响。

• 发表时间: 2002
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Bash-Babula,Judy;Toppmeyer,Deborah;Labassi,Marie;Reidy,Janice;Orlick,Michelle;Senzon,Rachelle;Alli,Elizabeth;Kearney,Thomas;August,David;Shih,Weichung;Yang,Jin-Ming;Hait,WilliamN
• 通讯作者: Hait,WilliamN