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To characterize extreme aged pet dogs as a first step in developing an animal model of exceptional longevity, we constructed lifetime medical histories for 345 Rottweiler dogs using information collected from owners and veterinarians. Extreme aged dogs (alive at the 95th percentile age at death for the study population, � 13.3 years) were compared with a usual longevity group (9‐10 years). Exceptional longevity in Rottweiler dogs was accompanied by a significant delay in the onset of major life-threatening diseases; 76% of extreme aged dogs remained free of all major diseases during the first 9 years of life. Only 19% of extreme aged dogs died of cancer versus 82% of dogs with usual longevity (p , .0001). The reduction in cancer mortality in oldest-old pet dogs mimics that seen in human centenarians and provides strong rationale for using this animal model to study comparative mechanisms of cancer resistance in the extreme aged.

The trace mineral selenium inhibits cancer development in a variety of experimental animal models. We used an in vivo canine model to evaluate the effects of dietary selenium supplementation on DNA damage in prostate tissue and on apoptosis in prostate epithelial cells. Sexually intact elderly male beagle dogs were randomly assigned to receive an unsupplemented diet (control group) or diets that were supplemented with selenium (treatment group), either as selenomethionine or as high-selenium yeast at 3 micro g/kg or 6 micro g/kg body weight per day for 7 months. The extent of DNA damage in prostate cells and in peripheral blood lymphocytes, as determined by the alkaline comet assay, was lower among the selenium-supplemented dogs than among the control dogs (prostate P

Steady state levels of DNA damage are substantial in vertebrate animals as a consequence of exposure to endogenous and environmental mutagens. DNA damage may contribute to organismal senescence and an increased risk for specific age-related diseases. In this study, we determined if treatment with the neuroactive adrenal steroid, dehydroepiandrosterone (DHEA), which exhibits antioxidant and anticarcinogenic properties in rodents, would reduce DNA damage in the brain and peripheral blood lymphocytes (PBLs) of elderly dogs. Elderly male dogs, physiologically equivalent to 59–69-year-old men, were randomly assigned to receive no treatment ( n =9 dogs) or DHEA at 100 mg/kg PO daily ( n =8 dogs). Extent of DNA damage in brain cells and PBLs was measured using alkaline comet assay. The effect of DHEA treatment on the susceptibility of PBLs to H 2 O 2 -induced DNA damage was also measured. We found that elderly male dogs receiving daily DHEA treatment for 7 months had significantly less DNA damage detectable in their brain compared to age-matched control dogs. After 7 months treatment, DHEA-treated dogs also had a significant reduction in DNA damage in PBLs compared to pre-treatment levels. We also found that PBLs of dogs treated with DHEA were more resistant to H 2 O 2 -induced DNA damage than PBLs of untreated dogs. Our results did not show that basal DNA damage in PBLs was strongly correlated with DNA damage within the brain. The results of this study suggest that DHEA supplementation can significantly reduce steady state levels of DNA damage in the mammalian brain. Further evaluation of DHEA as a neuroactive agent and its effects on DNA damage and gene expression in other tissues and species is warranted.

BACKGROUND Pet dogs and men share a vulnerability for the development of prostate carcinoma. The purpose of this study was to further characterize the clinical and pathologic features of spontaneous canine prostate carcinoma. METHODS A multiinstitutional, retrospective study was conducted using 76 dogs with prostate carcinoma that underwent postmortem evaluation. For each case, clinical and pathologic data were tabulated and hematoxylin/eosin-stained tissue sections from the primary tumor and metastatic lesions were evaluated. Prostatic carcinomas were subclassified based upon the presence of glandular, urothelial, squamoid, or sarcomatoid differentiation. We focused our analysis on dogs that differed with respect to morphologic features of the primary tumor, lifetime duration of testicular hormone exposure, and presence of skeletal metastases. RESULTS The vast majority of canine prostate carcinomas affected elderly sexually intact dogs or dogs that underwent surgical castration after sexual maturity. Adenocarcinoma was the most frequent histologic type, although more than half of canine prostate carcinomas exhibited intratumoral heterogeneity. In many cases, primary tumors showed mixed morphology, characterized by two or more types of differentiation. Duration of testicular hormone exposure was significantly different between dogs with adenocarcinoma and dogs with mixed morphology tumor, but did not appear to influence the frequency or pattern of metastases. Overall, gross metastases were present in 80% of dogs with prostate carcinoma. Skeletal metastases were present in 22% of cases, and the predominantly axial skeletal distribution of these lesions was similar to that reported in men with prostate carcinoma. Young dogs were at highest risk for development of skeletal metastases. CONCLUSIONS This study provides a more complete characterization of spontaneous prostate carcinoma of dogs in terms of morphologic heterogeneity, skeletal metastases, and the influence of testicular hormones. Prostate carcinoma in pet dogs provides an immunocompetent, autochthonous tumor system that mimics certain aspects of human prostate cancer. This spontaneous model may contribute to our understanding of the factors that regulate carcinogenesis within the aged prostate, and to the development of chemoprevention strategies or bone-targeted therapies. Prostate 45:173–183, 2000. © 2000 Wiley-Liss, Inc.

To move closer to the goal of individualized risk prediction for prostate cancer, we used an in vivo canine model to evaluate whether the susceptibility of peripheral blood lymphocytes (PBLs) to oxidative stress-induced DNA damage could identify those individuals with the highest prostatic DNA damage. This hypothesis was tested in a population of 69 elderly male beagle dogs after they had completed a 7-month randomized feeding trial to achieve the broad range of dietary selenium status observed in U.S. men. The alkaline Comet assay was used to directly compare the extent of DNA damage in PBLs with prostatic DNA damage in each dog. Using stepwise logistic regression, the sensitivity of PBLs to oxidative stress challenge with hydrogen peroxide (H2O2) predicted dogs in the highest tertile of prostatic DNA damage. Dogs with PBLs highly sensitive to H2O2 were 7.6 times [95% confidence interval (95% CI), 1.5-38.3] more likely to have high prostatic DNA damage than those in the H2O2-resistant group. This risk stratification was observed in multivariate analysis that considered other factors that might influence DNA damage, such as age, toenail selenium concentration, and serum testosterone concentration. Our data show that the sensitivity of PBLs to oxidative stress challenge, but not endogenous DNA damage in PBLs, provides a noninvasive surrogate marker for prostatic DNA damage. These findings lend support to the concept that oxidative stress contributes to genotoxic damage, and that oxidative stress challenge may stratify men for prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1906–10)

Daily supplementation with the essential trace mineral selenium significantly reduced prostate cancer risk in men in the Nutritional Prevention of Cancer Trial. However, the optimal intake of selenium for prostate cancer prevention is unknown. We hypothesized that selenium significantly regulates the extent of genotoxic damage within the aging prostate and that the relationship between dietary selenium intake and DNA damage is non-linear, i.e. more selenium is not necessarily better. To test this hypothesis, we conducted a randomized feeding trial in which 49 elderly beagle dogs (physiologically equivalent to 62-69-year-old men) received nutritionally adequate or supranutritional levels of selenium for 7 months, in order to mimic the range of dietary selenium intake of men in the United States. Our results demonstrate an intriguing U-shaped dose-response relationship between selenium status (toenail selenium concentration) and the extent of DNA damage (alkaline Comet assay) within the prostate. Further, we demonstrate that the concentration of selenium that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a new approach to bridge the gap between laboratory and human studies that can be used to select the appropriate dose of anticancer agents for large-scale human cancer prevention trials. From the U-shaped dose-response, it follows that not all men will necessarily benefit from increasing their selenium intake and that measurement of baseline nutrient status should be required for all individuals in prevention trials to avoid oversupplementation.

The role of the essential trace mineral selenium in human health and disease is currently a subject of intense interest. In particular, the possible cancer preventive effects of dietary selenium supplementation are now being investigated in several large, randomized trials. The association between selenium status, genotoxic damage, and cancer risk remains enigmatic because epidemiologic studies have failed to consistently link low selenium status with increased cancer risk in men and women. In this paper, we considered the evidence that there are sex-based differences in the anticarcinogenic effects of selenium in humans. We focused our review on prospective human studies in which the relationship between selenium status and cancer risk in men and women was directly compared. Results from cohort studies conducted in seven countries (Belgium, China, Finland, Japan, Netherlands, Norway, and United States) were used to assess the strength of association between low selenium status and the incidence of all cancers, sex-specific cancers, and cancers at particular anatomic sites. In general, the available data support the hypothesis that cancer risk in men is more profoundly influenced by selenium status than cancer risk in women. Factors contributing to the apparent difference in the effects of selenium on cancer incidence in men and women may include sex-based differences in the metabolism and/or tissue distribution of selenium, as well as sex- or gender-related factors that influence tumor biology. Studies are needed to further define the dose-response relationship between selenium and cancer risk in men and women. A more complete understanding of the mechanisms by which selenium modulates cancer initiation and progression is needed to optimize dietary selenium supplementation as a practical cancer preventive strategy. Ultimately, achieving the ambitious goal of cancer prevention may require sex- and gender-specific approaches.

Although experimental and clinical evidence suggest that endogenous sex hormones influence bone sarcoma genesis, the hypothesis has not been adequately tested in an appropriate animal model. We conducted a historical cohort study of Rottweiler dogs because they frequently undergo elective gonadectomy and spontaneously develop appendicular bone sarcomas, which mimic the biological behavior of the osteosarcomas that affect children and adolescents. Data were collected by questionnaire from owners of 683 Rottweiler dogs living in North America. To determine whether there was an association between endogenous sex hormones and risk of bone sarcoma, relative risk (RR) of incidence rates and hazard ratios for bone sarcoma were calculated for dogs subdivided on the basis of lifetime gonadal hormone exposure. Bone sarcoma was diagnosed in 12.6% of dogs in this cohort during 71,004 dog-months follow-up. Risk for bone sarcoma was significantly influenced by age at gonadectomy. Male and female dogs that underwent gonadectomy before 1 year of age had an approximate one in four lifetime risk for bone sarcoma and were significantly more likely to develop bone sarcoma than dogs that were sexually intact [RR +/-95% CI = 3.8 (1.5-9.2) for males; RR +/-95% CI = 3.1 (1.1-8.3) for females]. Chi(2) test for trend showed a highly significant inverse dose-response relationship between duration of lifetime gonadal exposure and incidence rate of bone sarcoma (P = 0.008 for males, P = 0.006 for females). This association was independent of adult height or body weight. We conclude that the subset of Rottweiler dogs that undergo early gonadectomy represent a unique, highly accessible target population to further study the gene:environment interactions that determine bone sarcoma risk and to test whether interventions can inhibit the spontaneous development of bone sarcoma.

Although the skeleton represents a potentially important target for the metastatic spread of carcinoma, the clinicopathologic features of skeletal metastases in dogs have not been documented extensively. In particular, no reports have focused on dogs in which skeletal metastasis was the initial clinical manifestation of their malignancy. Medical records were reviewed for dogs with skeletal carcinoma and cases were subdivided into 2 groups based upon the temporal relationship between the diagnosis of carcinoma and recognition of skeletal metastases. In 19 of 24 (79%) dogs, skeletal metastasis was the initial clinical manifestation of malignancy, and these dogs were studied in detail. Most affected dogs were elderly and weighted less than 25 kg. Thirty-six skeletal lesions were identified in 19 dogs. Skeletal metastases occurred most frequently in the axial skeleton and proximal long bones. Only 4 of 36 (11%) skeletal carcinomas occurred distal to the elbow or stifle. Mammary gland, prostate, and urinary bladder were the most common primary sites. In 11 of 19 (58%), dogs, the primary tumor could not be determined, and in 6 of these dogs, the primary tumor could not be identified despite complete postmortem evaluation. Physical examination and abdominal ultrasonography were most valuable in detecting the primary tumor. Although biopsy or fine-needle aspirate of skeletal lesions was essential in the diagnosis of skeletal carcinoma, these procedures did not yield definitive information on the primary tumor site. This report documents that the majority of skeletal metastases are diagnosed in dogs without a previous diagnosis of carcinoma. Detection of the primary tumor in these cases may be challenging, and skeletal metastases are frequently attributable to carcinoma of unknown origin.