Pilot Study--Cox2 Inhibitor in Invasive Bladder Cancer

试点研究——Cox2 抑制剂治疗侵袭性膀胱癌

• 批准号: 6405955
• 负责人: DEBORAH W KNAPP
• 金额: $ 31.33万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6405955
• 关键词: antineoplastics; apoptosis; bladder neoplasm; fibroblast growth factor; human subject; human therapy evaluation; isozymes; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; patient oriented research; prostaglandin endoperoxide synthase; prostaglandins; thromboxanes; transitional cell carcinoma; urine

Description: Invasive urinary bladder cancer kills more than 12,000 people each year in the United States. Most of those deaths are due to invasive transitional cell carcinoma (TCC) that has metastasized and is resistant to chemotherapy. Our long range goal is to develop more effective treatment for invasive TCC. Cyclooxygenase (Cox) inhibitors have induced apoptosis and caused regression of invasive TCC in animal studies. The antitumor activity of Cox inhibitors is thought to be due, at least in part, to inhibition of Cox and the resulting decrease in Cox products (prostaglandins and thromboxanes). The objectives of this application are to establish the effects of a cyclooxygenase-2 (cox-2) inhibitor in: (1) inducing tumor apoptosis and reducing urine bFGF concentration, and (2) controlling the concentration of Cox products in humans with invasive TCC. The central hypothesis is cox-2 inhibitors will block the synthesis of Cox products (thereby limiting concentrations of Cox products in the tumor) and will induce apoptosis in invasive TCC in humans. The central hypothesis is based on strong preliminary data showing antitumor activity of Cox inhibitors and a strong association between the Cox inhibitor-induced tumor regression and doubling of the apoptotic index in invasive TCC in canine studies. Reduction in urine bFGF concentration has also been associated with Cox inhibitor-induced tumor regression in animals, and will be a secondary endpoint in our proposed studies. In addition to being associated with tumor regression with Cox inhibitors, induction of apoptosis and inhibition of bFGF synthesis and release are important effects in control of cancer and response to cancer therapy. A multidisciplinary team has been assembled to perform a pilot study of the cox-2 inhibitor, celecoxib, in humans with muscle invasive TCC. The composition of the team will allow for rapid design and implementation of large-scale clinical trials, should the expected outcomes of the proposed studies occur. The hypothesis will be tested by pursuing two specific aims: (1) determine the activity of a cox- 2 inhibitor in inducing apoptosis in tumor tissue and reducing urine bFGF concentration in humans with invasive TCC, and (2) determine the extent to which a cox-2 inhibitor controls prostaglandin and thromboxane production in invasive TCC in people. The expectation is that the cox-2 inhibitor will control prostaglandin and thromboxane production, will induce tumor apoptosis, and will lower urine bFGF concentration in patients with invasive TCC. The proposed research is significant because it is expected to lead to a more effective approach to treating invasive TCC that will reduce mortality, increase quality of life, and reduce overall costs of the medical care of patients with invasive TCC.

描述：在美国，每年有12,000多人杀死12,000多人。这些死亡中的大多数是由于侵入性过渡细胞癌（TCC）引起的，该细胞癌（TCC）已转移并且对化学疗法具有抵抗力。我们的远距离目标是为侵入性TCC开发更有效的治疗方法。环氧酶（COX）抑制剂在动物研究中诱导凋亡并导致侵入性TCC的消退。 Cox抑制剂的抗肿瘤活性至少部分归因于Cox的抑制作用以及Cox产物（前列腺素和血栓烷）的降低。本应用的目的是在以下方面建立环氧合酶-2（COX-2）抑制剂的影响：（1）诱导肿瘤凋亡并降低尿液BFGF浓度，以及（2）控制人类具有侵入性TCC的人类Cox产物的浓度。中心假设是COX-2抑制剂将阻止COX产品的合成（从而限制肿瘤中Cox产物的浓度），并会诱导人类入侵性TCC的凋亡。中心假设基于强大的初步数据，显示了COX抑制剂的抗肿瘤活性以及Cox抑制剂诱导的肿瘤消退与犬科动物TCC中凋亡指数倍增之间的较强关联。尿液BFGF浓度的降低也与COX抑制剂诱导的动物肿瘤消退有关，这将是我们提出的研究中的第二端点。除了与COX抑制剂相关的肿瘤消退外，凋亡诱导和BFGF合成和释放的抑制作用也是控制癌症和对癌症治疗反应的重要作用。在患有肌肉浸润性TCC的人类中，已经组装了一个多学科团队，以对COX-2抑制剂Celecoxib进行试验研究。如果提出的研究的预期结果，团队的组成将允许快速设计和实施大规模的临床试验。该假设将通过追求两个具体目的来检验：（1）确定Cox-2抑制剂在诱导肿瘤组织凋亡中的活性，并降低具有浸润性TCC的人类中尿液BFGF浓度，（2）确定Cox-2抑制剂对Prostaglandin和Thromboxane boxboxane and Thromboxane in Invasive Tcc中的cox-2抑制剂的限制。期望COX-2抑制剂将控制前列腺素和血栓烷产生，将诱导肿瘤凋亡，并降低浸润性TCC患者的尿液BFGF浓度。拟议的研究非常重要，因为预计它将导致一种更有效的方法来治疗侵入性TCC，以降低死亡率，提高生活质量并降低侵入性TCC患者的医疗保健总成本。