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Perillyl Alcohol as a Chemopreventive Agent in N-Nitrosomethylbenzylamine-induced Rat Esophageal Tumorigenesis¹

Department of Pathology [B. W. L.], and Division of Environmental Health Sciences, School of Public Health and Comprehensive Cancer Center [R. N., P. S. C., A. G., R. A., W. F., G. D. S.], The Ohio State University, Columbus, Ohio 43210

Perillyl alcohol (POH) is a monoterpene found in lavender, spearmint, and cherries. Phase I clinical trials with this agent have shown a favorable toxicity profile and preliminary data indicate some chemotherapeutic efficacy in advanced cancers. Animal studies have demonstrated the ability of POH to inhibit tumorigenesis in the mammary gland, liver, and pancreas. Although the precise mechanism of action is unclear, POH has been shown to inhibit the farnesylation of small G-proteins, including Ras, up-regulate the mannose-6-phosphate receptor, and induce apoptosis. Previous studies in our laboratory using the rat model of squamous cell carcinoma of the esophagus have shown that a specific Ha-ras codon 12 mutation is important for tumor promotion and progression. Given the limited toxicity of POH in humans, its proven efficacy in several animal models and its potential to inhibit Ha-ras farnesylation, we conducted an animal study to evaluate the efficacy of POH as a chemopreventive agent for squamous cell carcinoma of the esophagus. Male Fischer-344 rats were treated s.c. with 0.25 mg/kg b.w. of N-nitrosomethylbenzylamine three times a week for 5 weeks. Three days after the final carcinogen dose, they were started either on control diet or diets containing 0.5 or 1.0% POH. At 25 weeks, the animals were sacrificed, and esophageal tumors were counted. Animals fed either dose of POH showed a significant increase in dysplasia when compared with controls (P < 0.05) and a nonsignificant trend toward increased tumor multiplicity. Additionally, 1.0% POH did not affect Ras membrane localization. These data indicate that POH has a weakly promoting effect early in nitrosamine-induced esophageal tumorigenesis and suggest that POH may not be an effective chemopreventive agent for esophageal cancer in humans.

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