This Project focuses on determining the cancer-preventive activity of isothiocyanates (ITCs) in the bladder. The hypothesis to be tested is that selected ITCs can suppress bladder carcinogenesis by disrupting multiple steps in the carcinogenic process: induction of Phase 2 enzymes, induction of apoptosis, and inhibition of cell proliferation. Molecular markers relevant to these biological events, as well as inhibition of tumorigenesis, will be studied. Bladder cancer is an important health problem; effective chemopreventive agents are needed. ITCs are abundant in vegetables and many are known anticarcinogens in non-bladder animal organs. Ingested ITCs are efficiently absorbed and almost exclusively excreted in urine as N-acetylcysteine conjugates (NAC-ITCs), which also are anticarcinogens and can release ITCs, making the bladder epithelium the most exposed tissue to ITCs/NAC-ITCs. The overwhelming majority of bladder cancers originate from the epithelial cells. Four dietary ITCs that displayed potent anti-carcinogenic activity in non-bladder animal organs and their NAC conjugates will be evaluated.
Aim 1 is designed to see whether ITCs or NAC-ITCs effectively induce critical Phase 2 detoxification enzymes, including glutathione transferase, quinone reductase-1, and UDPglucuronosyltransferase, whose deficiencies have been linked to increased bladder carcinogenesis.
Aim 2 will determine the protective efficacy of ITCs or NAC-ITCs against carcinogen-induced DNA damage in bladder epithelial cells, using total DNA adducts and unscheduled DNA synthesis (UDS) as markers. Imbalance between apoptosis and proliferation also is a risk factor of bladder cancer.
Aim 3 will determine whether ITCs or NAC-ITCs can correct the imbalance between apoptosis and proliferation associated with bladder carcinogenesis: Do ITCs or NAC-ITCs induce apoptosis and/or inhibit cell cycle progression in bladder cancer cells? If so, what is the underlying mechanism(s)? Aim 4 will evaluate in rivo the effect of orally administered ITCs on important biomarkers, including the Phase 2 enzymes described in Aim 1, apoptosis (TUNEL), and proliferation (PCNA) in the bladder epithelium of F344 rats.
Aim 5 will determine the efficacy of an orally administered ITC in inhibiting N-butyl-N- (4-hydroxybutyl)-nitrosamine-induced bladder tumorigenesis in F344 rats.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA080962-05
Application #
6681181
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Seifried, Harold E
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
5
Fiscal Year
2003
Total Cost
$215,426
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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Zhang, Yuesheng; Yao, Song; Li, Jun (2006) Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action. Proc Nutr Soc 65:68-75
Munday, Rex; Zhang, Yuesheng; Munday, Christine M et al. (2006) Structure-activity relationships in the induction of Phase II enzymes by derivatives of 3H-1,2-dithiole-3-thione in rats. Chem Biol Interact 160:115-22
Li, J; Yao, S; Zhang, Y (2005) The role of c-Jun in the AP-1 activation induced by naturally occurring isothiocyanates. Food Chem Toxicol 43:1373-80

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