BIOMARKERS FOR BLADDER CANCER CHEMOPREVENTION TRIALS

膀胱癌仍然是一个重要的公共卫生问题， 预计1997年将有54 000多人被确诊。 尽管 重要的进展，大约一半的患者诊断为 浅表疾病会复发，这些患者有 发展成肌肉侵袭性疾病的重大风险。 膀胱切除术 通常需要肌肉侵入性疾病。 鉴定 复发和进展风险高的个体因此是至关重要的， 但是目前的临床标记物是不完善的。 预防灾难 疾病进展的后果是一个更理想的目标。 本 最后，一些假定的化学预防剂已被确定。 然而，这些药物的临床研究和开发有限 因为缺乏确定疗效的标志物。 因此，本提案的目的是 是根据已知的疾病生物学， 可能是化学预防研究的中间标志物。 这里将对三个这样的标记进行评估。 第一个是删除 荧光原位杂交法测定9 p21染色体区域 （FISH）。 这些缺失是最常见和最早可识别的 膀胱癌的基因改变 第二种是过度表达 表皮生长因子受体（EGFR）。 这种过度表达已经被 在膀胱癌患者的组织学正常组织中发现 癌 最后一个标志物是8-OH-脱氧鸟苷（8-OHdG）。 这一标志 氧化性DNA损伤已被报道在尿中升高， 烟草滥用者，膀胱癌是一种与烟草有关的疾病。 最终的目标是开发出易于测量的标记物， 尿液或膀胱冲洗样本中。 在本提案中， 将在这样的样品中测定标记物，并与 正常和恶性组织来自同一个病人。 以这种方式，任何 将确认异常结果。 然后，标记测量将 在已经切除浅表肿瘤的个体中进行， 追踪疾病复发情况。 任何可检测到的异常 没有临床疾病可识别的时间将与 复发风险和复发时的标志物发现。

DESCRIPTION: Bladder cancer remains an important public-health problem with more 54,000 individuals predicted to be diagnosed in 1997. Despite important advances, approximately one half of the patients diagnosed with superficial disease will suffer a recurrence, and these patients have a significant risk for developing muscle invasive disease. Cystectomy is generally required for muscle invasive disease. Identification of individuals at high risk for recurrence and progression is thus critical, but current clinical markers are imperfect. Prevention of the dire consequences of disease progression is an even more desirable goal. To this end, a number of putative chemopreventive agents have been identified. Clinical investigation and development of these agents is, however, limited by lack of markers to determine efficacy. Thus, th purpose of this proposal is to identify and develop markers based on the known disease biology that may be intermediate markers for chemoprevention studies. Three such markers will be evaluated here. The first is deletion of the 9p21 chromosomal region as determined by fluorescence in situ hybridization (FISH). These deletions are the most common and earliest identifiable genetic alteration in bladder cancer. The second is overexpression of the epidermal growth factor receptor (EGFR). Such overexpression has been identified in the histologically normal tissue of patients with bladder cancer. The final marker is 8-OH-deoxyguanosine (8-OHdG). This marker of oxidative DNA damage has been reported to be elevated in the urine of tobacco abusers, and bladder cancer is a tobacco-related disease. The eventual goal is to develop markers that are easily measured in the urine or in bladder wash specimens. In this proposal, measurements for each marker will be determined in such samples and compared to measurements in normal and malignant tissue from the same patient. In this manner any abnormal findings will be validated. Marker measurements will then be performed in individuals who have had a superficial tumor resected and are being followed for disease recurrence. Any detectable abnormalities at the time when no clinical disease is identifiable will be correlated with the risk of recurrence and marker findings at the time of recurrence.