Pilot Study--Cox2 Inhibitor in Invasive Bladder Cancer

在美国，每年有超过12000人死于浸润性膀胱癌。这些死亡大多是由于侵袭性移行细胞癌（TCC）已经转移并且对化疗有耐药性。我们的长期目标是开发更有效的治疗侵袭性TCC的方法。在动物实验中，环氧合酶（Cox）抑制剂诱导细胞凋亡并引起侵袭性TCC的消退。Cox抑制剂的抗肿瘤活性被认为至少部分是由于对Cox的抑制以及由此导致的Cox产物（前列腺素和血栓烷）的减少。本应用的目的是确定环氧化酶-2 （Cox -2）抑制剂在以下方面的作用：(1)诱导肿瘤凋亡和降低尿bFGF浓度；(2)控制侵袭性TCC患者体内Cox产物的浓度。中心假设是Cox -2抑制剂会阻断Cox产物的合成（从而限制肿瘤中Cox产物的浓度），并诱导人类侵袭性TCC的细胞凋亡。中心假设是基于强有力的初步数据，这些数据显示Cox抑制剂具有抗肿瘤活性，并且在犬的侵袭性TCC研究中，Cox抑制剂诱导的肿瘤消退与凋亡指数加倍之间存在很强的关联。在动物实验中，尿bFGF浓度的降低也与Cox抑制剂诱导的肿瘤消退有关，这将是我们提出的研究的次要终点。除了通过Cox抑制剂与肿瘤消退相关外，诱导细胞凋亡和抑制bFGF的合成和释放是控制癌症和对癌症治疗反应的重要作用。一个多学科的研究小组已经组织起来，对cox-2抑制剂塞来昔布在肌肉侵袭性TCC患者中的应用进行初步研究。如果拟议研究的预期结果出现，该团队的组成将允许快速设计和实施大规模临床试验。该假设将通过追求两个特定目标来验证：(1)确定cox-2抑制剂在诱导肿瘤组织凋亡和降低侵袭性TCC患者尿bFGF浓度中的活性；(2)确定cox-2抑制剂在侵袭性TCC患者中控制前列腺素和凝血素产生的程度。我们期望cox-2抑制剂能够控制前列腺素和凝血素的产生，诱导肿瘤凋亡，降低浸润性TCC患者的尿bFGF浓度。这项研究具有重要意义，因为它有望找到一种更有效的方法来治疗侵袭性TCC，从而降低死亡率，提高生活质量，并降低侵袭性TCC患者的总体医疗费用。

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.