MOLECULAR MECHANISMS OF ANTIMICROTUBULE AGENTS

描述：(改编自《调查员摘要》)1998年，18万 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癌症的标准 (III)或转移性(IV期)非小细胞肺癌(NSCLC)。AS 对于其他DNA损伤剂，铂是最有效的抗肿瘤药物 含有野生型53。结合临床研究的令人印象深刻的早期结果 含铂的新型抗微管药物使西南肿瘤学小组 启动400名患者的随机第三阶段临床试验(SWOG-9509) 紫杉烷(紫杉醇)和紫杉醇两类抗微管药物的比较 长春花碱(长春瑞滨)，每个与一个铂结合。这其中的每一个 抗微管药物在体外的分子作用机制 这可能解释了临床结果：a)两者都通过 抗细胞凋亡蛋白bcl2和b)的磷酸化和失活 在含有突变型p53的肿瘤中是活跃的。但是，这些活动可能 紫杉烷和长春花碱之间的不同基于效力，特异性， 或尚不确定的因素。此外，紫杉烷还显示出独特的临床应用。 铂类耐药非小细胞肺癌患者特定分子的活性 紫杉烷和长春花碱的反应相关基因图谱不同。 包含了这间书房的武器。具体的目标是检查突变 P53和B-微管蛋白的状态以及与肿瘤通路的相关性将 接受检查。肿瘤标本从入院患者那里获得的前处理 将对SWOG-9509进行研究。突变状态将通过单链检测 构象多态(SSCP)、微阵列和酵母(如果需要)。 增殖细胞将通过免疫组织化学(IHC)染色确定 片段DNA末端标记Mib1和凋亡细胞。Bcl2的表达， Bclx(L)、bax和p27用免疫组化方法检测，bcl2：bax和p27的比例。 BCL-x(L)；BAX由人工和数字评分建立。分子数据将是 与患者的反应和存活率相关，并回顾统计 意义。这个多学科的研究团队特别 能够充分利用这一重要的患者资源来执行 这种假说驱动的分子-临床相关性。这项研究可能会导致 更好地选择任何一种联合治疗的患者，导致 改善了护理质量和临床结果。

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.