MOLECULAR MECHANISMS OF ANTIMICROTUBULE AGENTS

抗微管剂的分子机制

• 批准号: 2908933
• 负责人: Charles A Coltman
• 金额: $ 18.98万
• 依托单位: CANCER THERAPY AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-06 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2908933
• 关键词: BCL2 gene /protein; cis platinum compound; clinical research; combination chemotherapy; drug interactions; gene mutation; human subject; human therapy evaluation; immunocytochemistry; lasers; lung neoplasms; microtubules; molecular pathology; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; outcomes research; p53 gene /protein; paclitaxel; single strand conformation polymorphism; statistics /biometry; vinca alkaloids

DESCRIPTION: (adapted from the investigator's abstract) In 1998, 180,000 Americans will be diagnosed with lung cancer and there will be 160,000 deaths, more than from breast, prostate and colon cancer combined. Platinum-based therapy has been accepted as a standard for treatment of locally advanced (Stage III) or metastatic (Stage IV) non-small cell lung cancer (NSCLC). As with other DNA-damaging agents, platinums are most effective against tumors containing wild-type 53. Impressive early results of clinical studies combining new antimicrotubule agents with a platinum led the Southwest Oncology Group to initiate a 400 patient randomized Phase III clinical trial (SWOG-9509) comparing two classes of antimicrotubule agents, the taxanes (paclitaxel) and vinca alkaloids (vinorelbine), each combined with a platinum. Each of these antimicrotubule agents demonstrates molecular mechanisms of action in vitro which may explain the clinical results: a) both induce apoptosis through phosphoylation and inactivation of the antiapoptosis protein Bcl2 and b) both are active in tumors that contain mutant p53. However, these activities may differ between the taxanes and vinca alkaloids based on potency, specificity, or as yet undetermined factors. Additionally, taxanes show unique clinical activity in patients with platinum-refractory NSCLC particular molecular profiles of response-related genes will differ between the taxane and vinca containing arms of this study. The specific aims are to examine the mutational status of p53 and B-tubulin and correlate the data with the tumor pathways will be examined. Tumor specimens obtained pretreatment from patients entered in SWOG-9509 will be studied. Mutational status will be examined by single-strand conformation polymorphism (SSCP), microarray and yeast if warranted. Proliferating cells will be identified by immunohistochemical (IHC) staining of Mib1 and apoptotic cells by end-labeling of fragmented DNA. Expression of Bcl2, Bcl-x(l), Bax and p27 will be assayed by IHC and rations of Bcl2:Bax and Bcl-x(l);Bax established by manual and digital scoring. Molecular data will be correlated with patient response and survival, and reviewed for statistical significance. This multidisciplinary research team is particularly well-positioned to optimize use of this important patient resource to perform this hypothesis-driven, molecular-clinical correlation. This study may lead to a better selection of patients for either combination therapy, leading to improved quality of care and clinical outcome.

描述：（改编自研究者摘要）1998年，18万人 美国人将被诊断出患有肺癌，将有16万人死亡， 比乳腺癌前列腺癌和结肠癌的总和还要多铂基 治疗已被接受为治疗局部晚期 （III期）或转移性（IV期）非小细胞肺癌（NSCLC）。作为 与其他DNA损伤剂一起，铂类药物对肿瘤最有效 含有野生型53.令人印象深刻的早期临床研究结果， 新的抗微管药物与铂导致西南肿瘤组， 启动400例患者随机III期临床试验（SWOG-9509） 比较两类抗微管剂，紫杉烷（紫杉醇）和 长春花生物碱（长春瑞滨），每一种都与铂结合。这一切成功都 抗微管剂在体外证实了分子作用机制 这可以解释临床结果：a）两者都通过以下途径诱导细胞凋亡： 抗凋亡蛋白Bcl 2的磷酸化和失活，和B）两者 在含有突变型p53的肿瘤中有活性。然而，这些活动可能 紫杉烷和长春花生物碱之间的区别基于效力，特异性， 或尚未确定的因素。此外，紫杉烷类显示出独特的临床 在铂类难治性NSCLC患者中的活性 紫杉烷和长春花之间的反应相关基因谱将不同 包含本研究的手臂。具体的目的是检查突变 p53和B-微管蛋白的状态，并将数据与肿瘤途径相关联， 接受检查。从入组患者中获得的治疗前肿瘤标本 将研究SWOG-9509。将通过单链抗体检测突变状态。 构象多态性（SSCP），微阵列和酵母，如果需要的话。 将通过免疫组织化学（IHC）染色鉴定增殖细胞， Mib 1和凋亡细胞的DNA片段的末端标记。Bcl 2的表达， Bcl-x（l）、Bax和p27将通过IHC测定，并且Bcl 2：Bax和p27的比率将通过免疫组织化学法测定。 Bcl-x（l）;Bax通过手动和数字评分建立。分子数据将是 与患者反应和生存期相关，并进行统计学审查 意义这个多学科的研究团队， 充分利用这一重要的患者资源， 这种假设驱动的分子临床相关性。这项研究可能会导致 更好地选择患者进行联合治疗， 提高护理质量和临床结果。