The last four years of this program were devoted toward three principal objectives: (a) to examine the structure-activity relationships for inhibition of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus; (b) to identify the P450 enzyme(s) responsible for the metabolism of NMBA in the rat esophagus, and to determine the effects of isothiocyanates on its/their activity(s); and (c) to identify inhibitors of tumor promotion/progression in the rat esophagus. With respect to the first objective, 3-phenylpropyl isothiocyanate (PPITC) was found to be a more effective inhibitor of NMBA-esophageal tumorigenesis than phenethyl isothiocyanate (PEITC) reported previously. However, the longer chain isothiocyanate (PHITC) actually enhanced NMBA-esophageal tumorigenesis. With respect to the second objective, our current data indicate that one or more cytochrome P450 enzymes of the 2A subfamily are involved in the metabolism of NMBA in the rat esophagus. To determine the precise mechanism of actions of PEITC and PPITC, it is necessary to know which P450(s) are responsible for NMBA metabolism. With respect to the third objective, PEITC, calcium, sulindac and ellagic acid were evaluated for their ability to inhibit tumor promotion/progression in the rat esophagus; all compounds were found to be inactive, with the exception of the high concentration of ellagic acid. An important goal of our research is to identify effective inhibitors of tumor promotion/progression in the esophagus, for these inhibitors could be useful in the prevention of esophageal tumor development in humans. Our recent finding that PPITC is an exceptional inhibitor of NNN-induced tumorigenesis provides a basis for the further study of the inhibitory effects of PPITC and related compounds on NNN-induced esophageal tumorigenesis as well as a basis for a toxicity study of PPITC. Therefore, our specific aims are: (1) To confirm that CYP2A3 or a closely related CYP2A enzyme is present in the rat esophagus and that his P450 efficiently metabolizes NMBA; (2) To further identify inhibitors of tumor promotion/progression in the rat esophagus; (3) To evaluate combinations of inhibitors of tumor initiation (i.e., PEITC) and of promotion/progression for their relative efficacy in inhibiting rat esophageal tumorigenesis; (4) To compare the chemopreventative efficacies of PEITC, PPITC, and their N-acetylcysteine conjugates on NNN-induced esophageal tumorigenesis using various biomarkers as endpoints; and (5) To evaluate the effects of PPITC in a 13-week toxicity study conducted in F344 rats.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA046535-12S1
Application #
6102417
Study Section
Project Start
1999-03-05
Project End
2000-01-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Stoner, Gary D; Wang, Li-Shu; Chen, Tong (2007) Chemoprevention of esophageal squamous cell carcinoma. Toxicol Appl Pharmacol 224:337-49
Hudson, Tamaro S; Stoner, Gary D; Morse, Mark A et al. (2005) Comparison of phenethyl and 6-phenylhexyl isothiocyanate-induced toxicity in rat esophageal cell lines with and without glutathione depletion. Toxicol Lett 155:427-36
Liston, Beth W; Nines, Ronald; Carlton, Peter S et al. (2003) Perillyl alcohol as a chemopreventive agent in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. Cancer Res 63:2399-403
Gopalakrishnan, Rajaram; Gupta, Ashok; Carlton, Peter S et al. (2002) Functional role of cytochrome p-450 2a3 in N-nitrosomethylbenzylamine metabolism in rat esophagus. J Toxicol Environ Health A 65:1077-91
Carlton, Peter S; Gopalakrishnan, Rajaram; Gupta, Ashok et al. (2002) Piroxicam is an ineffective inhibitor of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus. Cancer Res 62:4376-82
Gupta, A; Nines, R; Rodrigo, K A et al. (2001) Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat. J Natl Cancer Inst 93:990-8
Hudson, T S; Carlton, P S; Gupta, A et al. (2001) Investigation of the enhancement of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis by 6-phenylhexyl isothiocyanate. Cancer Lett 162:19-26
Liston, B W; Gupta, A; Nines, R et al. (2001) Incidence and effects of Ha-ras codon 12 G-->A transition mutations in preneoplastic lesions induced by N-nitrosomethylbenzylamine in the rat esophagus. Mol Carcinog 32:1-8
Boone, C W; Stoner, G D; Bacus, J V et al. (2000) Chemoprevention with theaflavins of rat esophageal intraepithelial neoplasia quantitatively monitored by image tile analysis. Cancer Epidemiol Biomarkers Prev 9:1149-54
Chung, F L; Jiao, D; Getahun, S M et al. (1998) A urinary biomarker for uptake of dietary isothiocyanates in humans. Cancer Epidemiol Biomarkers Prev 7:103-8