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The Dietary Charred Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine Acts as Both a Tumor Initiator and Promoter in the Rat Ventral Prostate

Departments of ¹ Pathology, ² The Sidney Kimmel Comprehensive Cancer Center, and the ³ Brady Urological Research Center at Johns Hopkins University School of Medicine, Baltimore, Maryland; and ⁴ Department of Urology, Osaka University, Osaka, Japan

Requests for reprints: Angelo M. De Marzo, Room 153, Bunting-Blaustein Cancer Research Building, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Baltimore, MD 21231-1000. Phone: 410-614-5686; Fax: 410-502-9817; E-mail: ademarz{at}jhmi.edu.

Exposure of Fisher344 rats to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine in cooked meat, causes cancer in the rat ventral prostate, while sparing the dorsolateral and anterior lobes. Uncovering the molecular mechanisms of the lobe specificity of PhIP-induced rat prostate cancer may provide clues to the pathogenesis of human prostate cancer, which is also lobe selective. We examined the prostate and other organs for mutation frequencies using transgenic Fisher344 rats (Big Blue rats) after PhIP treatment. After PhIP treatment for as early as 4 weeks, the colon, spleen, seminal vesicles, and all lobes of the prostate had significantly elevated mutation frequencies compared with the saline-treated control group, and the differences became even greater after 8 weeks. G:C T:A transversions were the predominant type of mutation. After 8 weeks of treatment with PhIP, the Ki-67 index was increased (P < 0.001) in the ventral prostate, but not in the dorsolateral or anterior prostate. An increase in the number of stromal mast cells and macrophages was seen in the ventral prostate, but not in the other prostatic lobes. The apoptotic index also increased in the ventral lobe only. The increased proliferation and cell death in response to PhIP indicates that in addition to PhIP acting as an "initiator" of cancer, PhIP is also acting like an organ- and lobe-specific tumor "promoter." The prostate lobe-specific infiltration of mast cells and macrophages in response to PhIP suggests a potential new mechanism by which this dietary compound can increase cancer risk—by prompting inflammation. [Cancer Res 2007;67(3):1378–84]

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