Investigation of the enhancement of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis by 6-phenylhexyl isothiocyanate.
Previous studies in our laboratory have shown that 6-phenylhexyl isothiocyanate (PHITC), enhances N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats while the shorter chain analogs, phenylethyl isothiocyanate (PEITC), and 3-phenylpropyl isothiocyanate (PPITC), inhibit NMBA-induced esophageal tumorigenesis. To test the hypothesis that PHITC influences the promotional stage of esophageal tumorigenesis, groups of 22-27 rats were dosed with vehicle or NMBA three times a week for 5 week, and fed a modified AIN-76A diet containing PHITC at concentrations of 0.0, 1.0, and 2.5 micromol/g. At the 25th week, the rats were killed, esophagi harvested and tumors counted. In the groups that received NMBA+PHITC, apparent but statistically insignificant increases in tumor multiplicity of 32 and 42% were found in comparison to rats treated with NMBA alone. A higher frequency of dysplastic lesions was found in rats treated with NMBA+2.5 micromol/g PHITC (71%) when compared to rats treated with NMBA only (12%). To test whether PHITC increased cellular proliferation, we evaluated proliferating cell nuclear antigen (PCNA) expression by immunohistochemistry. While there were no significant increases in PCNA staining in rats treated with NMBA+PHITC compared to rats treated with NMBA only, rats treated with PHITC only had a significantly higher PCNA index compared to untreated controls. Expression of cyclin D1, another biomarker of proliferation, was analyzed by semi-quantitative reverse transcription-polymerase chain reaction. There were no significant increases in cyclin D1 expression in groups treated with NMBA+PHITC compared to the group treated with NMBA only. Thus, while the data suggest a promotional effect by PHITC as manifested by a significant increase in dysplastic leukoplakia by the high dose of PHITC and an increase in the PCNA index by PHITC alone, PHITC does not appear to have a significant effect on esophageal cell proliferation.
Hudson
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Division of Environmental Health Sciences, The Ohio State University School of Public Health, CHRI Rm. 1148, 300 West Tenth Ave., Columbus, OH 43210, USA.
Carlton
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Gupta
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Stoner
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GD
Morse
M A
MA
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D019938:Cyclin D1 / Q000032:analysis; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000633:toxicity; D004938:Esophageal Neoplasms / Q000139:chemically induced* / Q000473:pathology; D017879:Isothiocyanates / Q000633:toxicity*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D017879:Isothiocyanates; D018809:Proliferating Cell Nuclear Antigen; C073279:6-phenylhexyl isothiocyanate; D019938:Cyclin D1; C014707:nitrosobenzylmethylamine; D004128:Dimethylnitrosamine