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Rapid Regression of Squamous Cell Hyperplasia and Slow Regression of Basal Cell Hyperplasia in the Forestomach of F344 Rats Treated with N-Methyl-N'-nitro-N-nitrosoguanidine and/or Butylated Hydroxyanisole¹

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

Cell kinetics of reversible and persistent forestomach lesions induced by the genotoxic agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and/or the nongenotoxic antioxidant butylated hydroxyanisole (BHA) was investigated. A total of 184 male F344 rats were divided into four groups: Group 1 given an initial single gastric intubation of MNNG received 2% BHA diet from the third wk to the 26th wk and then basal diet; Group 2 receiving 2% BHA without MNNG initiation; Group 3 given MNNG alone; and Group 4 serving as a nontreated control. Rats were sequentially sacrificed at 6, 16, 26, 30, and 46 wk. Bromodeoxyuridine was administered either as a single i.p. injection (100 mg/kg of body weight) 1 h before killing or continuously via an osmotic minipump (120 µg/h) for 1, 3, or 7 days prior to sacrifice, in each case labeled cells being detected by immunohistochemistry. Squamous cell hyperplasia (SCH) and basal cell hyperplasia (BCH), each characterized by different phenotypic keratin expression, were induced in Groups 1 to 3. After withdrawal of BHA, rapid regression of SCH and extremely slow regression of BCH were observed. Papillomas and squamous cell carcinomas developed irreversibly in Groups 1 and 3, BHA significantly (P < 0.01) enhancing the incidence of SCC in Group 1. Flash and continuous bromodeoxyuridine labeling revealed SCH to consist of cells of high mitotic activity and short life span, whereas BCH consisted of cells with low mitotic activity and long life span. In addition, highly labeled areas were observed in SCH after cessation of BHA feeding in Group 1 without regression, and similar lesions were also evident in Group 3. The results suggest that rapid regression of SCH and slow regression of BCH reflect different cell kinetic patterns and that highly labeled areas after release from stimulating agents might be preneoplastic changes related to cancer development.

¹ This work was supported by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture and the Ministry of Health and Welfare of Japan and by a Grant-in-Aid from the Ministry of Health and Welfare for a Comprehensive 10-Year Strategy for Cancer Control, Japan.

² To whom requests for reprints should be addressed.

Received 4/ 9/90. Accepted 9/26/90.