Chemopreventive Effect of a Xanthine Oxidase Inhibitor, 1′‐Acetoxychavicol Acetate, on Rat Oral Carcinogenesis

The effect of a xanthine oxidase inhibitor, 1′‐acetoxychavicol acetate (ACA), on 4‐nitroquinoline 1‐oxide (4‐NQO)‐induced oral carcinogenesis was investigated in male F344 rats. All rats except those in the ACA‐alone and untreated groups were given 4‐NQO (20 ppm) in the drinking water for 8 weeks to induce oral cancer. Starting 1 week before the 4‐NQO exposure, animals were fed diet containing 100 ppm or 500 ppm ACA for 10 weeks, followed by the basal diet without ACA for 22 weeks. Other groups were fed the diet containing ACA at 100 ppm or 500 ppm for 22 weeks, starting 1 week after the cessation of 4‐NQO exposure. The remaining groups consisted of rats given 500 ppm ACA alone or untreated rats. At the termination of the experiment (32 weeks), the incidences of tongue neoplasms and preneoplastic lesions, polyamine levels in the tongue tissue, and cell proliferation activity estimated in terms of 5‐bromodeoxyuridine (BrdU)‐labeling index and by morphometric analysis of silver‐stained nucleolar organizer regions’ protein (AgNORs) were compared among the groups. Feeding of ACA at the two doses during initiation or postinitiation significantly decreased the development of tongue carcinoma (93–100% reduction, P< 0.001) and preneoplasia (43–50% reduction for hyperplasia and 34–48% reduction for dysplasia, P<0.05). There were no such lesions in rats fed ACA alone or those in the untreated control group. The number of AgNORs per cell nucleus was significantly decreased by feeding of ACA at a high dose (500 ppm) (29% inhibition, P<0.05). The BrdU‐labeling index was also reduced by dietary administration of ACA (23–32% inhibition, P<0.01). In addition, ACA feeding reduced tongue polyamine levels (35–40% inhibition, P<0.05). These results indicate that ACA inhibited rat oral carcinogenesis, and such inhibition might be related to suppression of cell proliferation in the oral mucosa by the xanthine oxidase inhibitor.