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Protection from Carcinogen-induced Murine Bladder Carcinoma by Interferons and an Oral Interferon-inducing Pyrimidinone, Bropirimine¹

Departments of Human Oncology [E. C. B., Y. A. S., E. E., G. T. B.] and Medicine [E. C. B.], University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792, and the Department of Cancer and Viral Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001 [W. W.]

Interferons (IFNs) have established activities as antivirals and inhibitors of viral and transplantable tumors. To establish whether IFNs or their inducers can affect induction of carcinogenesis in vivo, the bladder-specific carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) was administered in the diet at 0.11 or 0.13% (w/w) to female C3H/He mice beginning at 7 weeks of age. Mice treated with the IFN-inducing bropirimine [2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone] i.p. twice a week for 14 weeks starting on day 30 of start of FANFT feeding developed fewer transitional cell carcinomas (TCC) than mice treated with the vehicle. Bropirimine (200 mg/kg twice a week) orally resulted in even greater effectiveness: 6 of 43 bladders with TCC for bropirimine-treated mice versus 24 of 39 for control glycine buffer-treated mice (P < 0.01, ² test). Mice treated i.p. daily on days 29 through 210 with 5,000 units of ß interferon (specific activity, 2.0 x 10⁸ units/mg) had 0 of 15 TCC while control mice had 7 of 13 TCC (P < 0.001). Bladders of untreated mice were also significantly heavier than those of ß interferon- or bropirimine-treated mice. This dose of IFN treatment was confirmed as effective in a second experiment, in which mice were treated daily on days 30–223 with 5,000 units /ß interferon (specific activity, 1.2 x 10⁷ units/mg). This resulted in 4 of 25 bladders with TCC versus 24 of 39 for control mice (P < 0.001). A higher dose of IFN (50,000 units /ß interferon daily) was toxic; 24 of 30 mice died within 2 months. IFN and an IFN inducer, bropirimine, inhibited development and progression of FANFT-induced bladder TCC in vivo and thus may have roles as chemopreventive modalities.

¹ Supported in part by grants from NIH (CA-20432), the American Cancer Society, the Upjohn Company, and Triton Biosciences. E. C. B. is an American Cancer Society Professor of Clinical Oncology.

² To whom requests for reprints should be addressed, at the Department of Human Oncology, University of Wisconsin Clinical Cancer Center, K4/414 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.

Received 7/ 6/89. Revised 10/23/89. Accepted 11/14/89.