DEVELOPMENT OF AN MDR-1 RESISTANCE-REVERSAL ASSAY

MDR-1 耐药逆转测定的开发

• 批准号: 3493453
• 负责人: John P Fruehauf
• 金额: $ 5万
• 依托单位: ONCOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-24 至 1994-02-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3493453
• 关键词: cis platinum compound; cyclosporines; flow cytometry; gene expression; human therapy evaluation; human tissue; immunocytochemistry; method development; multidrug resistance; neoplasm /cancer chemotherapy; ovary neoplasms; paclitaxel; prognosis; tissue /cell culture; verapamil

Currently, assays for MDR-1 expression are for research purposes only. This study will determine if measurement of MDR-1 expression by flow cytometry can be performed as a routine clinical assay, and if such an assay can predict the clinical response of patients treated with Taxol for ovarian cancer. Furthermore, the value of testing in vitro resistance- reversal by verapamil and cyclosporin analogue will also he assessed. Phase I of this project will evaluate the feasibility of acquiring and testing the tissues, and obtain initial data on patient outcome. Phase II will evaluate a large number of patients to test the statistical significance of these assays. Expression of MDR-1 by intrinsically drug resistant tumors such as renal, colon, adrenal, and pancreatic cancers indicates the broad spectrum of tumor types where drug resistance may be related in part to a specific drug-efflux mechanism. The notion that MDR-1 expression is clinically related to treatment failure has been supported by Salmon's group at the University of Arizona, where recent clinical trials indicated that MDR reversal in refractory patients expressing MDR-1 could improve patient outcome. Both verapamil and cyclosporin have been found to sensitize patients to doxorubicin and vincristine. However, use of these reversing agents is associated with systemic toxicity, and not all drug resistant patients expressing MDR-1 will benefit from verapamil or cyclosporin treatment. To more fully realize the clinical utility of MDR-resistance reversal it will be necessary to study the relationship between MDR-1 expression and patient outcome for a large number of patients. This study will focus on the development of a clinical assay to evaluate patient tumors for MDR-1 expression, in vitro drug resistance, and resistance reversal by verapamil and cyclosporin analogue. Patients to be evaluated in Phase I of this project are part of GOG-118, and have untreated stage 3 or 4 epithelial ovarian cancer. They will be treated on protocol GOG-132 with cisplatin, taxol or taxol plus cisplatin. Each patient specimen will be tested for MDR-1 expression by flow cytometry and histochemistry. In vitro response to cisplatin, Taxol, or the combination, in the presence and absence of verapamil and cyclosporin analogue will be determined by the Kern tritiated thymidine incorporation assay. Patient outcome will be determined at second look laparotomy and correlated to the assay results.

目前，MDR-1表达的测定仅用于研究目的。 本研究将确定是否通过流式细胞术测量MDR-1表达 细胞计数可以作为常规临床测定来进行，并且如果这样的细胞计数可以作为常规临床测定来进行，则细胞计数可以作为常规临床测定来进行。 检测可以预测患者的临床反应与紫杉醇治疗， 卵巢癌此外，体外抗药性测试的价值- 还将评估维拉帕米和环孢菌素类似物的逆转作用。 该项目的第一阶段将评估收购的可行性， 测试组织，并获得关于患者结果的初始数据。二期 将对大量患者进行评估，以检验统计学 这些分析的意义。MDR-1基因在内源性药物中的表达 耐药肿瘤，如肾癌、结肠癌、肾上腺癌和胰腺癌 表明肿瘤类型的广谱性，其中耐药性可能是 部分与特定的药物外排机制有关。MDR-1的概念 表达在临床上与治疗失败相关， 由亚利桑那大学的Salmon小组进行的研究， 临床试验表明，在表达MDR-1的难治性患者中， 可以改善患者的预后。维拉帕米和环孢菌素都是 发现它能使病人对阿霉素和长春新碱敏感。但使用 这些逆转剂与全身毒性有关，而不是 所有表达MDR-1的耐药患者将从维拉帕米中获益 或环孢菌素治疗。为了更充分地实现 MDR-耐药逆转将有必要研究其关系 MDR-1表达与患者预后之间的关系， 患者本研究将集中于开发一种临床检测方法， 评估患者肿瘤的MDR-1表达、体外耐药性， 维拉帕米和环孢菌素类似物可逆转耐药。患者 在该项目的第一阶段进行评估是GOG-118的一部分， 未经治疗的3期或4期上皮性卵巢癌。他们将接受治疗， 方案GOG-132与顺铂、紫杉醇或紫杉醇加顺铂。每个 将通过流式细胞术检测患者标本的MDR-1表达， 组织化学对顺铂、紫杉醇或其组合的体外反应， 在存在和不存在维拉帕米和环孢菌素类似物的情况下， 通过克恩氚化胸苷掺入试验测定。患者 结果将在第二次剖腹探查时确定，并与 分析结果。

项目成果

Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin.

• 发表时间: 1998-02
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: E. Mechetner;A. Kyshtoobayeva;S. Zonis;Hun-Gu Kim;R. Stroup;R. García;R. Parker;J. Fruehauf