BIOCHEMICAL AND CYTOGENETIC MARKERS IN RETINOBLASTOMA

视网膜母细胞瘤的生化和细胞遗传学标志物

• 批准号: 2683511
• 负责人: WILLIAM Francis BENEDICT
• 金额: $ 15.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683511
• 关键词: biomarker; bladder neoplasm; cyclins; gene induction /repression; genetic markers; guanine nucleotide binding protein; immunocytochemistry; neoplasm /cancer genetics; neoplastic process; northern blottings; nucleic acid sequence; oncoprotein p21; radiobiology; retinoblastoma; retinoblastoma protein; southern blotting; tissue /cell culture; tumor antigens; tumor suppressor genes; tumor suppressor proteins; western blottings

DESCRIPTION: Recent results from the laboratory with others indicate that altered RB or p53 status and particularly both together are strong candidates to become prognostic markers for progression and overall survival in superficial and advanced bladder cancer (and likely other tumor types as well). The confirmation of these initial results could lead to these markers being used to develop different therapeutics strategies leading to improved survival in certain cases and a more conservative approach to bladder cancer therapy in others (i.e., bladder preservation). Individuals with abnormally strong nuclear RB staining have also been found to have a similarly poor prognosis as those with absent RB protein expression, although the molecular basis for this is presently unknown. In addition preliminary data suggest that small cell carcinomas of the lung (SCLCs) and atypical carcinomas can be distinguished by their RB status, which in turn has important diagnostic and therapeutic implications, since they receive different therapies. Our Specific Aims therefore include: 1. To undertake large prospective studies on both superficial and advanced bladder cancer to determine if RB or p53 status in a given tumor and especially both together can be used as bona fide prognostic markers for tumor progression and overall survival. The possibility that RB and/or p53 status can be related to chemotherapeutic response will also be evaluated as well as whether other genes in the RB and p53 pathway including p16, p21, cyclin D1 and cyclin E. 2. To determine the mechanisms or molecular basis (? hyperphosphorylation) by which certain bladder tumors show an abnormal percentage of malignant cells with strong RB nuclear staining. 3. To determine both in cell culture and in vivo if bladder tumor lines with loss of RB function are more sensitive to radiation, which is suggested from the initial clinical results. 4. To verify in a large prospective that RB status can distinguish between SCLCs and atypical carcinomas. 5. To examine other genes in the RB pathway including p16, Cyclin D1, Cyclin E, are important in the pathogenesis of other specific tumor types in which the direct loss of RB function is rare. Immunohistochemical analysis will primarily be utilized for the prognostic and diagnostic studies based on the previous findings. However, Southern, Northern and Western analysis will also be done for certain genes and specific tumor types. In addition DNA sequencing and other molecular biology techniques will be used when appropriate as well. Routine techniques to measure cytotoxicity, and apoptosis produced by radiation both in culture and in vivo will also be utilized.

描述：实验室与其他实验室的最新结果表明 RB 或 p53 状态发生改变，特别是两者一起作用很强 候选者成为进展和总体生存的预后标志物 在浅表性和晚期膀胱癌（以及可能的其他肿瘤类型，如 出色地）。 这些初步结果的确认可能会导致这些 标记物被用来开发不同的治疗策略，导致 在某些情况下提高生存率并采用更保守的方法 其他人的膀胱癌治疗（即膀胱保留）。 个人 核 RB 染色异常强的情况也被发现有 与缺乏 RB 蛋白表达的患者预后相似， 尽管目前尚不清楚其分子基础。 此外 初步数据表明，小细胞肺癌（SCLC）和 非典型癌可以通过其 RB 状态来区分，而 RB 状态又 具有重要的诊断和治疗意义，因为它们接受 不同的疗法。 因此，我们的具体目标包括： 1. 承担 针对浅表性膀胱癌和晚期膀胱癌的大型前瞻性研究 确定给定肿瘤中的 RB 或 p53 状态，尤其是两者同时存在 可用作肿瘤进展的真正预后标志物 总体生存率。 RB 和/或 p53 状态可能相关的可能性 还将评估对化疗的反应以及其他情况是否 RB 和 p53 途径中的基因，包括 p16、p21、cyclin D1 和 cyclin E。 2. 确定机制或分子基础（？过度磷酸化） 某些膀胱肿瘤显示恶性比例异常 具有强 RB 核染色的细胞。 3. 在单元格中确定两者 培养和体内如果RB功能丧失的膀胱肿瘤系更多 对辐射敏感，这是从最初的临床结果表明的 结果。 4. 从大的角度验证RB状态是否可以 区分 SCLC 和非典型癌。 5.检查其他 RB 通路中的基因包括 p16、Cyclin D1、Cyclin E，在 其他特定肿瘤类型的发病机制，其中直接损失 RB功能很少见。 免疫组织化学分析将主要用于预后 以及基于先前发现的诊断研究。 然而，南方， 还将对某些基因进行北方和西方分析 特定的肿瘤类型。 此外 DNA 测序和其他分子 适当时也会使用生物学技术。 常规 测量细胞毒性和辐射产生的细胞凋亡的技术 也将在培养和体内使用。