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Effect of Calcium Channel Blockers on Gastric Carcinogenesis and Caerulein Enhancement of Gastric Carcinogenesis Induced by N-Methyl-N'-nitro-N-nitrosoguanidine in Wistar Rats

Departments of Gastrointestinal Oncology [M. T., H. I., M. B., A. N., H. U.] and Pathology [H. T.], The Center for Adult Diseases, Osaka, 3-3, Nakamichi 1-chome, Higashinari-ku, Osaka 537, Japan

The effects of the organic calcium channel blocker verapamil and the inorganic calcium channel blocker MgCl₂ on gastric carcinogenesis, on caerulein enhancement of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and on the labeling index of gastric mucosa were investigated in inbred Wistar rats. After 25 weeks of treatment with N-methyl-N'-nitro-N-nitrosoguanidine (50 µg/ml p.o.), rats received one of the following alternate-day injections: caerulein (2 µg/kg body weight, s.c.), MgCl₂ (150 mg/kg, s.c.), verapamil (20 mg/kg body weight, i.p.), caerulein (2 µg/kg body weight, s.c.) plus MgCl₂ (150 mg/kg body weight, s.c.), or caerulein (2 µg/kg body weight, s.c.) plus verapamil (20 mg/kg body weight, i.p.). At Week 52, prolonged administration of caerulein had significantly increased the incidence and number of adenocarcinomas in the glandular stomach and the incidence of gastric cancers that penetrated through or beyond the muscle layer. Concomitant administration of MgCl₂ significantly attenuated the enhancing effect of caerulein on gastric carcinogenesis. Combined administration of caerulein and verapamil did not affect the incidence and number of gastric cancers but significantly reduced the incidence of cancers penetrating through or beyond the muscle layer. Administration of MgCl₂ or verapamil alone had no influence on gastric carcinogenesis. Rats treated with caerulein had a significantly elevated labeling index of the antral mucosa which was significantly decreased by concomitant administration of MgCl₂ and/or of verapamil, as compared with the labeling index observed after treatment with caerulein alone. Either MgCl₂ or verapamil alone had no influence on the labeling index of the antral mucosa. These findings indicate that caerulein enhances gastric carcinogenesis and that MgCl₂ and verapamil attenuate this enhancement. These findings also indicate that calcium may play an important role in caerulein enhancement of gastric carcinogenesis.

¹ To whom requests for reprints should be addressed.

Received 9/25/89. Revised 12/18/89.

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