Pilot Study--Cox2 Inhibitor in Invasive Bladder Cancer

在美国，侵袭性膀胱癌每年导致超过12，000人死亡。这些死亡中的大多数是由于侵袭性移行细胞癌（TCC）已经转移并对化疗耐药。我们的长期目标是为侵袭性TCC开发更有效的治疗方法。在动物实验中，环氧合酶（考克斯）抑制剂可诱导细胞凋亡并使侵袭性TCC消退。考克斯抑制剂的抗肿瘤活性被认为至少部分是由于对考克斯的抑制以及由此导致的考克斯产物（异莲心素和血栓烷）的减少。本申请的目的是确定环加氧酶-2（cox-2）抑制剂在以下方面的作用：（1）诱导肿瘤细胞凋亡和降低尿bFGF浓度，和（2）控制患有侵袭性TCC的人中的考克斯产物的浓度。中心假设是cox-2抑制剂将阻断考克斯产物的合成（从而限制肿瘤中考克斯产物的浓度）并将诱导人类侵袭性TCC中的细胞凋亡。中心假设基于强有力的初步数据，这些数据显示考克斯抑制剂的抗肿瘤活性，以及考克斯抑制剂诱导的肿瘤消退与犬研究中侵袭性TCC中凋亡指数加倍之间的强相关性。尿液bFGF浓度的降低也与动物中考克斯肿瘤诱导的肿瘤消退相关，并将成为我们拟定研究的次要终点。除了与使用考克斯抑制剂的肿瘤消退相关之外，诱导细胞凋亡和抑制bFGF合成和释放在控制癌症和对癌症治疗的反应中是重要的作用。一个多学科小组已经成立，进行考克斯-2抑制剂，塞来昔布，在人类肌肉侵袭性TCC的试点研究。该团队的组成将允许快速设计和实施大规模临床试验，如果拟议研究的预期结果发生。将通过追求两个具体目标来检验该假设：（1）确定考克斯- 2抑制剂在患有侵袭性TCC的人中诱导肿瘤组织中的细胞凋亡和降低尿bFGF浓度的活性，和（2）确定考克斯-2抑制剂在多大程度上控制人中侵袭性TCC中前列腺素和血栓素的产生。期望考克斯-2抑制剂将控制前列腺素和血栓素的产生，将诱导肿瘤细胞凋亡，并将降低侵袭性TCC患者的尿bFGF浓度。这项拟议的研究意义重大，因为它有望导致一种更有效的方法来治疗侵袭性TCC，这将降低死亡率，提高生活质量，并降低侵袭性TCC患者的整体医疗费用。

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.