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Chemoprevention of experimental bladder cancer
R C Moon1, C J Detrisac, C F Thomas
1IIT Research Institute, Chicago, Illinois 60616.
Abstract:
The chemopreventive efficacy of several compounds was evaluated in the N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer model using C57BL/6 x DBA/2F1 (BDF) male mice. Compounds were administered in a defined semipurified diet (AIN-76-A) either as single agents or in combination. As single agents and at the doses employed, 2-alpha-difluoromethylornithine (DFMO), piroxicam, oltipraz, and sodium molybdate effectively inhibited the incidence of transitional cell carcinoma (TCC). 4-Hydroxyphenyl retinamide (4-HPR) was ineffective. Body weight gain and survival was not affected by the doses of agents used. Combinations of two agents which increased efficacy were 4-HPR+DFMO, DFMO+piroxicam, 4-HPR+oltipraz, and DFMO+oltipraz. Three-agent combinations which showed enhanced efficacy against TCC induction were 4-HPR+Na molybdate+DFMO, 4-HPR+DFMO+piroxicam, and 4-HPR+DFMO+oltipraz. Although the three-agent combinations were, for the most part, no more effective than the two-agent combinations at the doses employed, all combination regimens significantly reduced bladder cancer incidence even when single agent administration did not.
Insights
Several compounds showed chemopreventive efficacy against bladder cancer in mice. Combinations of agents, particularly those including 2-alpha-difluoromethylornithine (DFMO), significantly reduced tumor incidence.
Area of Science:
- Oncology
- Chemoprevention
- Carcinogenesis
Background:
- Urinary bladder cancer remains a significant health concern.
- N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) is a known inducer of transitional cell carcinoma (TCC) in animal models.
- Identifying effective chemopreventive agents is crucial for cancer prevention strategies.
Purpose of the Study:
- To evaluate the chemopreventive efficacy of single agents and combinations against OH-BBN-induced TCC in male mice.
- To identify synergistic effects of compound combinations in preventing bladder cancer.
- To assess the impact of tested compounds on animal body weight and survival.
Main Methods:
- Utilized the N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) induced urinary bladder cancer model in C57BL/6 x DBA/2F1 (BDF) male mice.
- Administered single agents and combinations of 2-alpha-difluoromethylornithine (DFMO), piroxicam, oltipraz, sodium molybdate, and 4-hydroxyphenyl retinamide (4-HPR) via a semipurified diet (AIN-76-A).
- Monitored tumor incidence, body weight gain, and survival rates.
Main Results:
- Single agents DFMO, piroxicam, oltipraz, and sodium molybdate effectively inhibited TCC incidence; 4-HPR was ineffective.
- Combinations of 4-HPR+DFMO, DFMO+piroxicam, 4-HPR+oltipraz, and DFMO+oltipraz demonstrated increased efficacy.
- Three-agent combinations (e.g., 4-HPR+Na molybdate+DFMO) showed enhanced efficacy, though not significantly more than two-agent combinations.
- All combination regimens significantly reduced bladder cancer incidence, even when single agents were ineffective.
Conclusions:
- Combination therapy with chemopreventive agents can significantly enhance efficacy in preventing bladder cancer.
- DFMO, piroxicam, oltipraz, and sodium molybdate show promise as single agents or in combination for bladder cancer chemoprevention.
- Further research into optimal combinations and dosages is warranted for clinical application.