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Protection from carcinogen-induced murine bladder carcinoma by interferons and an oral interferon-inducing
E C Borden1, Y A Sidky, E Ertürk
1Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Abstract:
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 less than 0.01, x2 test). Mice treated i.p. daily on days 29 through 210 with 5,000 units of beta interferon (specific activity, 2.0 x 10(8) units/mg) had 0 of 15 TCC while control mice had 7 of 13 TCC (P less than 0.001). Bladders of untreated mice were also significantly heavier than those of beta 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 alpha/beta interferon (specific activity, 1.2 x 10(7) units/mg). This resulted in 4 of 25 bladders with TCC versus 24 of 39 for control mice (P less than 0.001). A higher dose of IFN (50,000 units alpha/beta 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.
Insights
Interferons (IFNs) and bropirimine, an IFN inducer, were investigated for their ability to prevent bladder cancer. Both IFNs and bropirimine significantly inhibited the development of transitional cell carcinomas (TCC) in mice exposed to a carcinogen, suggesting their potential as chemopreventive agents.
Area of Science:
- Oncology
- Immunology
- Carcinogenesis Research
Background:
- Interferons (IFNs) are known for antiviral and antitumor activities.
- The role of IFNs and their inducers in preventing carcinogenesis in vivo remains to be fully established.
- N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) is a known bladder-specific carcinogen.
Purpose of the Study:
- To investigate the potential of interferons (IFNs) and an IFN inducer, bropirimine, in preventing the induction of bladder cancer in a mouse model.
- To evaluate the efficacy of bropirimine and beta interferon (IFN-β) and alpha/beta interferon (IFN-α/β) in inhibiting the development and progression of FANFT-induced bladder transitional cell carcinomas (TCC).
Main Methods:
- Female C3H/He mice were administered the bladder carcinogen FANFT in their diet.
- Mice were treated with either bropirimine (intraperitoneal or oral) or IFNs (IFN-β or IFN-α/β) at various doses and schedules.
- Tumor incidence and bladder weights were assessed and compared between treatment groups and controls.
Main Results:
- Bropirimine treatment significantly reduced the incidence of bladder TCC compared to vehicle controls.
- Both beta interferon (IFN-β) and alpha/beta interferon (IFN-α/β) treatments resulted in a significant reduction in TCC development.
- Higher doses of IFN-α/β were found to be toxic, leading to increased mortality in mice.
Conclusions:
- Interferons (IFNs) and the IFN inducer bropirimine demonstrated significant chemopreventive effects against FANFT-induced bladder TCC in vivo.
- These findings suggest that IFNs and bropirimine may hold potential as chemopreventive agents for bladder cancer.
- Further research is warranted to explore the therapeutic window and mechanisms of action for these agents.