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Effect of Flurbiprofen and 16,16-Dimethyl Prostaglandin E₂ on Gastrointestinal Tumorigenesis Induced by N-Methyl-N'-nitro-N-nitrosoguanidine in Rats: Glandular Epithelium of Stomach and Duodenum¹

Department of Surgery [T. L.] and Gastrointestinal Service, Department of Medicine [E. E. D.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021 Department of Nutrition, Rutgers University, New Brunswick, New Jersey 08903 [R. A. K.]; and Department of Surgery, Cornell University Medical College, New York, New York 10021 [J. J. D.]

The effect of an exogenous synthetic prostaglandin analogue, 16,16-dimethyl prostaglandin E₂ (16,16-dm-PGE₂), as well as the effect of endogenous prostaglandin synthesis inhibition by a cyclooxygenase inhibitor, flurbiprofen, on chemically induced gastric carcinogenesis has been investigated in rats. Carcinogenesis was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS:70-25-7). Animals were divided into six groups: Group I, treatment with MNNG alone; Group II, treatment with 16,16-dm-PGE₂ plus MNNG; group III, treatment with flurbiprofen plus MNNG; Group IV, treatment with 16,16-dm-PGE₂ alone; Group V, treatment with flurbiprofen alone; and Group VI, controls.

Treatment with high doses of MNNG resulted in rapid development of malignant tumors originating from the glandular epithelium of the stomach and duodenum in animals of all groups receiving the carcinogen. The first gastric adenocarcinoma infiltrating the muscularis proper was detected after 139 days in an animal treated with a combination of MNNG and flurbiprofen. The incidence of infiltrating adenocarcinoma and the incidence of all neoplastic lesions of the glandular stomach were both significantly higher in animals treated with a combination of MNNG and flurbiprofen compared with treatment by MNNG alone or in combination with 16,16-dm-PGE₂ (P < 0.05 and P < 0.001). The difference in tumor incidence between the last two groups was not significant.

The first duodenal adenocarcinoma was detected on Day 114 in another animal of the group treated with MNNG plus flurbiprofen. When compared with the group treated with MNNG plus 16,16-dm-PGE₂, significantly more animals developed duodenal adenocarcinoma when treated with MNNG plus flurbiprofen (P < 0.005) or with MNNG alone (P < 0.05).

Results of this study indicate that inhibition of endogenous prostaglandin synthesis favors development of adenocarcinoma in the glandular stomach of rats. Vice versa, the addition of an exogenous prostaglandin analogue inhibits the development of duodenal adenocarcinoma. This protective effect of prostaglandins may be due to an increase of the thickness of the mucus gel covering the glandular epithelium, thereby preventing access of carcinogen to the mucosa.

¹ This is the second paper in a series.

² Present address: Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-6900 Heidelberg, Federal Republic of Germany. To whom requests for reprints should be addressed.

Received 8/30/88. Revised 8/21/89. Accepted 9/26/89.

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