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ラット膀胱発癌における細胞周期関連分子の発現および遺伝子変異の検索：李祺家、山本晋史、市原敏夫、鰐淵英機、福島昭治（大阪市大・医・1病理）

Alterations of Cell Cycle Related Elements in Multistage or Complete Bladder Carcinogenesis in the F344 Rats Following the Administration of Genotoxic or Non-genotoxic Carcinogens: Chyi Chia R. Lee, Toshio Ichihara, Shinji Yamamoto, Hideki Wanibuchi, Chiyo Kimura, and Shoji Fukushima (First Dept. of Pathol., Osaka City Univ. Med. Sch.)

[BACKBROUND] The experiment was to assess the stage specific events in rat bladder carcinogenesis following the administration of non-genotoxic carcinogens uracil and sodium L-ascorbate (NaAsA) or the genotoxic carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). The expression of the G1 cyclins, CDK inhibitors and p53 in addition to mutations of p53, H-ras and K-ras in tumors were examined.
[METHODS] 120, male, Fisher 344 rats were divided into four groups and administered carcinogens until sacrificed at weeks 18, 32 or 46. Group 1 were initiated with 0.05% BBN for 4 weeks, followed by 3% uracil in diet; group 2 were administered 3% uracil beginning at week 5; group 3 were initiated with 0.05% BBN for 4 weeks, followed by 5% NaAsA; group 4 were administered 0.05% BBN continuously throughout the experiment. mRNA levels of the cell cycle regulators were assessed by multiplex RT-PCR. Mutations of p53 (exons 5-9), H-ras (exons 1-2) and K-ras (exons 1-2) were assessed by PCR-SSCP and DNA sequencing.
[RESULTS] Continuous administration of the genotoxic carcinogen BBN, but not uracil or NaAsA, to rats results in frequent p53 mutations in bladder tumors (> 50%). K-ras and H-ras mutations were very rare in all four groups. Overexpression of cyclin D1 (> 2 fold) and reduced expressions of the CDK inhibitors p21^WAF1/Cip1 (< 1/2 fold) and p27^KIP1 (<1/2 fold) were observed in rat bladder tumors of all four groups.
[CONCLUSIONS] Continuous administration of BBN likely imposes a selective advantage to rat bladder tumors with p53 mutations. Administration of non-genotoxic carcinogens, whether alone or after initiation with BBN, rarely induced p53 mutations in tumors. Overexpression of cyclin D1 and reduced expression of p21^WAF1/Cip1 and p27^KIP1 are frequent in tumors induced by genotoxic or non-genotoxic carcinogens.