Oral perfluorooctane sulfonate (PFOS) lessens tumor development in the APCmin mouse model of spontaneous familial adenomatous polyposis.

BACKGROUND: Colorectal cancer is the second most common cause of cancer deaths for both men and women, and the third most common cause of cancer in the U.S. Toxicity of current chemotherapeutic agents for colorectal cancer, and emergence of drug resistance underscore the need to develop new, potentially less toxic alternatives. Our recent cross-sectional study in a large Appalachian population, showed a strong, inverse, dose-response association of serum perfluorooctane sulfonate (PFOS) levels to prevalent colorectal cancer, suggesting PFOS may have therapeutic potential in the prevention and/or treatment of colorectal cancer. In these preliminary studies using a mouse model of familial colorectal cancer, the APCmin mouse, and exposures comparable to those reported in human populations, we assess the efficacy of PFOS for reducing tumor burden, and evaluate potential dose-response effects. METHODS: At 5-6 weeks of age, APCmin mice were randomized to receive 0, 20, 250 mg PFOS/kg (females) or 0, 10, 50 and 200 mg PFOS/kg (males) via their drinking water. At 15 weeks of age, gastrointestinal tumors were counted and scored and blood PFOS levels measured. RESULTS: PFOS exposure was associated with a significant, dose-response reduction in total tumor number in both male and female mice. This inverse dose-response effect of PFOS exposure was particularly pronounced for larger tumors (r2 for linear trend = 0.44 for males, p's <0.001). CONCLUSIONS: The current study in a mouse model of familial adenomatous polyposis offers the first experimental evidence that chronic exposure to PFOS in drinking water can reduce formation of gastrointestinal tumors, and that these reductions are both significant and dose-dependent. If confirmed in further studies, these promising findings could lead to new therapeutic strategies for familial colorectal cancer, and suggest that PFOS testing in both preventive and therapeutic models for human colorectal cancer is warranted.

Evaluation of an improved sustained-release buprenorphine formulation for use in mice.

OBJECTIVE: To evaluate analgesic effects of an improved sustained-release buprenorphine (BUP-SR) formulation administered to mice. ANIMALS: 36 male Swiss-Webster mice. PROCEDURES: Mice were assigned to each of 3 treatment groups (n = 12 mice/group). Treatments were administered SC (vehicle [control treatment], 1.5 mg of buprenorphine hydrochloride [BUP-HCl]/kg, and 1.5 mg of BUP-SR/kg). Mice were evaluated (total activity, gastrointestinal tract motility, respiratory rate, cataleptic behavior, and tall-flick and hot plate nociception tests) to determine behavioral and physiologic responses at 4, 24, and 48 hours after treatment administration. Body weight and respiratory rate were measured before and at each time point after treatment administration. RESULTS: SC administration of BUP-SR resulted in significant antinociception effects for 48 hours for the hot plate and tall-flick nociception tests without substantial adverse effects. Gastrointestinal tract motility and total activity were higher at 4 hours for mice receiving BUP-SR than for mice receiving the vehicle, but values were the same between these groups at 24 and 48 hours. The BUP-SR group had a lower respiratory rate than did the control group at all times after treatment administration. Mice treated with BUP-SR had no significant changes in body weight during the study, whereas mice treated with BUP-HCl had a significant decrease in body weight at 24 and 48 hours. CONCLUSIONS AND CLINICAL RELEVANCE: BUP-SR administration resulted in antinociception effects for 48 hours. Results of this study indicated that the improved BUP-SR formulation could be safely administered SC and conferred superior analgesia, compared with that for BUP-HCl, in mice.