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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA093011-01
Application #
6405955
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Xie, Heng
Project Start
2001-09-01
Project End
2003-05-31
Budget Start
2001-09-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$313,345
Indirect Cost
Name
Purdue University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Hahn, Noah M; Bonney, Patty L; Dhawan, Deepika et al. (2012) Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma: a novel epigenetic approach to human urothelial carcinoma drug development. J Urol 187:302-9
Dhawan, Deepika; Craig, Bruce A; Cheng, Liang et al. (2010) Effects of short-term celecoxib treatment in patients with invasive transitional cell carcinoma of the urinary bladder. Mol Cancer Ther 9:1371-7
Dhawan, Deepika; Jeffreys, Antonella Borgatti; Zheng, Rong et al. (2008) Cyclooxygenase-2 dependent and independent antitumor effects induced by celecoxib in urinary bladder cancer cells. Mol Cancer Ther 7:897-904
Mohammed, Sulma I; Dhawan, Deepika; Abraham, Shaji et al. (2006) Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects. Mol Cancer Ther 5:329-36