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  • Author or Editor: James P. Farese x
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Abstract

Objective—To determine the effect of pamidronate disodium on the in vitro viability of osteosarcoma cells and non-neoplastic cells from dogs.

Sample Population—3 osteosarcoma and 1 fibroblast cell lines derived from dogs.

Procedure—Cell counts and cell viability assays were performed in cultures of osteosarcoma cells (POS, HMPOS, and COS31 cell lines) and fibroblasts after 24, 48, and 72 hours of incubation with pamidronate at concentrations of 0.001 to 1,000µM or with no drug (control treatment). Percentage viability was determined in cell samples for each concentration of pamidronate and each incubation time. A DNA fragmentation analysis was performed to assess bisphosphonate- induced apoptosis.

Results—Osteosarcoma cell viability decreased significantly in a concentration- and time-dependent manner at pamidronate concentrations ranging from 100 to 1,000µM, most consistently after 48 and 72 hours' exposure. In treated osteosarcoma cells, the lowest percentage cell viability was 34% (detected after 72 hours' exposure to 1,000µM pamidronate). Conversely, 72 hours' exposure to 1,000µM pamidronate did not significantly reduce fibroblast viability (the lowest percentage viability was 76%). After 72 hours of exposure, pamidronate did not cause DNA fragmentation in POS or HMPOS cells.

Conclusions and Clinical Relevance—Results indicate that pamidronate may have the potential to inhibit osteosarcoma growth in dogs, possibly through a nonapoptotic mechanism. The clinical relevance of these in vitro findings remains to be determined, but administration of pamidronate may potentially be indicated as an adjuvant treatment in chemotherapeutic protocols used in dogs. (Am J Vet Res 2005;66: 885–891)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether thalidomide inhibits the growth of primary and pulmonary metastatic canine osteosarcoma in mice after xenotransplantation.

Animals—Athymic nude mice.

Procedure—Canine osteosarcoma cells were injected SC in 50 mice. Mice were randomly placed into the following groups: control group (n = 13; DMSO [drug vehicle] alone [0.1 mL/d, IP]); low-dose group (12; thalidomide [100 mg/kg, IP]), mid-dose group (13; thalidomide [200 mg/kg, IP]); and high-dose group (12; thalidomide [400 mg/kg, IP]). Starting on day 8, treatments were administered daily and tumor measurements were performed for 20 days. On day 28, mice were euthanatized and primary tumors were weighed. Lungs were examined histologically to determine the number of mice with metastasis and tumor emboli. Mean area of the pulmonary micrometastatic foci was determined for mice from each group.

Results—Primary tumor size and weight were not significantly different among groups. The number of mice in the mid-dose (200 mg/kg) and high-dose (400 mg/kg) groups with micrometastasis was significantly less than the number of control group mice; however, the number of mice with tumor emboli was not affected by thalidomide treatment. Size of micrometastasis lesions was not affected by thalidomide treatment.

Conclusions and Clinical Relevance—Mean area of micrometastases was not affected by treatment; however, growth of micrometastases had not yet reached an angiogenesis-dependent size. Although thalidomide did not affect growth of primary tumors in mice after xenotransplantation of canine osteosarcoma cells, our findings indicate that thalidomide may interfere with the ability of embolic tumor cells to complete the metastatic process within the lungs. ( Am J Vet Res 2004;65:659–664)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether exposure of canine osteosarcoma cells to deracoxib or piroxicam results in decreased viability, whether the cytotoxic effects of deracoxib and piroxicam involve induction of apoptosis, and whether deracoxib is a more potent inhibitor of osteosarcoma cell growth than piroxicam.

Sample Population—1 fibroblast and 3 osteosarcoma cell lines.

Procedure—Cell counts and viability assays were performed using osteosarcoma cells (POS, highly metastatic POS, and canine osteosarcoma cell 31) and fibroblasts after 72 hours of incubation with deracoxib at concentrations of 0.5µM to 500µM or piroxicam at concentrations of 1µM to 1,000µM. Percentage viability was determined for each concentration. A DNA fragmentation analysis was performed to assess drug-induced apoptosis.

Results—Concentration of deracoxib required for 50% inhibition of cell viability (IC50) was reached in all 3 osteosarcoma cell lines and ranged from 70 to 150µM, whereas the IC50 for piroxicam was only reached in the POS cell line at 500µM. Neither deracoxib nor piroxicam induced sufficient toxicity in fibroblasts to reach an IC50. Exposure of osteosarcoma cells to cytotoxic concentrations of deracoxib and piroxicam did not result in DNA fragmentation.

Conclusions and Clinical Relevance—Intermediate and high concentrations of deracoxib and high concentrations of piroxicam were cytotoxic to osteosarcoma cells; neither drug inhibited cell viability at typical plasma concentrations in dogs. Deracoxib inhibited viability of cells at concentrations that did not affect fibroblast viability. There was no evidence of apoptosis induction for either drug; however, only 1 cell line was evaluated for apoptosis induction and only for a limited selection of drug concentrations. (Am J Vet Res 2005;66:1961–1967)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To describe a percutaneously controlled static hydraulic urethral sphincter (SHUS) and evaluate urodynamic effects of the SHUS in canine cadavers.

Sample Population—Cadavers of 6 adult female dogs.

Procedure—Cadavers were obtained immediately after dogs were euthanatized. Baseline maximal urethral closure pressure (MUCP) and cystourethral leak point pressure (CLPP) were measured by use of a urethral pressure profilometer. An SHUS system was constructed by use of a silicone vascular occluder and subcutaneous infusion port. The SHUS system was then placed around the pelvic urethra in each cadaver. Measurements of MUCP and CLPP were repeated after varying occlusion of the SHUS (0%, 25%, and 50% occlusion). Baseline MUCP and CLPP values were compared with values obtained at 0%, 25%, and 50% occlusion of the SHUS by use of repeatedmeasures ANOVA.

Results—Mean ± SD MUCP for canine cadavers was 7 ± 1.3 cm H2O at baseline, which increased to 127 ± 53 cm H2O after 50% occlusion of the SHUS. Mean CLPP was 11 ± 8.6 cm H2O at baseline, which increased to 73 ± 38 cm H2O after 50% occlusion of the SHUS. Mean MUCP and CLPP were significantly associated with the amount of occlusion.

Conclusions and Clinical Relevance—The SHUS had positive effects on MUCP and CLPP in canine cadavers. Therefore, additional evaluation of the SHUS in live dogs is warranted. ( Am J Vet Res 2004; 65:283–288)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To describe outcomes for small-breed dogs with appendicular osteosarcoma.

Design—Multi-institutional retrospective case series.

Animals—51 small-breed dogs.

Procedures—Records from participating Veterinary Society of Surgical Oncology members were searched for dogs that weighed ≤ 15 kg (33 lb) with a histologic diagnosis of appendicular osteosarcoma. The Kaplan-Meier method was used to determine median survival times (MSTs), and Cox regression was performed to identify variables associated with survival time.

Results—Tumors were most commonly located on the humerus (n = 15) and femur (14). Of the 51 study dogs, 9 were treated nonsurgically, 16 underwent amputation of the affected limb only, and 26 underwent curative-intent treatment, with MSTs of 112, 257, and 415 days, respectively. The MST did not differ significantly between dogs in the amputation-only and curative-intent groups. For dogs in the nonsurgical group, MST decreased significantly as the tumor histologic score increased. For dogs in the amputation-only group, MST decreased as body weight increased.

Conclusions and Clinical Relevance—For the small-breed dogs with appendicular osteosarcoma of the present study, tumor histologic grade and mitotic index were subjectively lower and MST following amputation of the affected limb without adjuvant chemotherapy was longer, compared with those for similarly affected larger dogs. Results indicated no significant advantage in MST for dogs that underwent curative-intent treatment versus dogs that underwent amputation only, and further investigation of the importance of adjuvant chemotherapy is warranted.

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To investigate the effects of bevacizumab, a human monoclonal antibody against vascular endothelial growth factor, on the angiogenesis and growth of canine osteosarcoma cells xenografted in mice.

Animals—27 athymic nude mice.

Procedures—To each mouse, highly metastasizing parent osteosarcoma cells of canine origin were injected into the left gastrocnemius muscle. Each mouse was then randomly allocated to 1 of 3 treatment groups: high-dose bevacizumab (4 mg/kg, IP), low-dose bevacizumab (2 mg/kg, IP), or control (no treatment). Tumor growth (the number of days required for the tumor to grow from 8 to 13 mm), vasculature, histomorphology, necrosis, and pulmonary metastasis were evaluated.

Results—Mice in the high-dose bevacizumab group had significantly delayed tumor growth (mean ± SD, 13.4 ± 3.8 days; range, 9 to 21 days), compared with that for mice in the low-dose bevacizumab group (mean ± SD, 9.4 ± 1.5 days; range, 7 to 11 days) or control group (mean ± SD, 7. 2 ± 1.5 days; range, 4 to 9 days). Mice in the low-dose bevacizumab group also had significantly delayed tumor growth, compared with that for mice in the control group.

Conclusions and Clinical Relevance—Results indicated that bevacizumab inhibited growth of canine osteosarcoma cells xenografted in mice, which suggested that vascular endothelial growth factor inhibitors may be clinically useful for the treatment of osteosarcoma in dogs.

Impact for Human Medicine—Canine osteosarcoma is used as a research model for human osteosarcoma; therefore, bevacizumab may be clinically beneficial for the treatment of osteosarcoma in humans.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To compare the accuracy of the extended- hip radiographic (EHR) score, the distraction index (DI), and the dorsolateral subluxation (DLS) score for identifying hip dysplasia in dogs at 8 months of age.

Design—Cohort study

Animals—129 Labrador Retrievers, Greyhounds, and Labrador Retriever-Greyhound crossbreds.

Procedure—Radiography was performed when dogs were 8 months of age. Dogs were euthanatized at 8 to 36 months of age; hip dysplasia was diagnosed at the time of necropsy on the basis of results of a gross examination of the articular cartilage of the hip joints for signs of osteoarthritis.

Results—The EHR score, DI, and DLS score at 8 months of age were all significantly correlated with degree of cartilage degeneration at necropsy. Sensitivity and specificity of using EHR score at 8 months of age to diagnose hip dysplasia (scores > 3 were considered abnormal) were 38 and 96%, respectively; sensitivity and specificity of using DI (values > 0.7 were considered abnormal) were 50 and 89%; and sensitivity and specificity of using DLS score (scores ≤ 55% were considered abnormal) were 83 and 84%.

Conclusions and Clinical Relevance—Results suggested that specificities of the 3 methods for diagnosing hip dysplasia in dogs at 8 months of age were similar. However, the DLS score had higher sensitivity, indicating that there were fewer false-negative results. (J Am Vet Med Assoc 2001;219:1242–1246)

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To compare the bone mineral density (BMD) of the proximal portion of the femur in dogs with and without early osteoarthritis secondary to hip dysplasia.

Animals—24 dogs (3 Greyhounds, 6 Labrador-Greyhound crossbreeds, and 15 Labrador Retrievers).

Procedure—Computed tomography (CT) of the pelvis, including a bone-density phantom, was performed for each dog. Centrally located transverse CT slices and a computer workstation were used to identify 16 regions of interest (ROIs) in the proximal portion of the femur. For each ROI, the mean Hounsfield unit value was recorded; by use of the bone-density phantom and linear regression analysis, those values were converted to equivalent BMD (eBMD). Mean eBMD values for the subchondral and nonsubchondral ROIs in dogs with and without osteoarthritis (determined at necropsy) were compared. A mixed-model ANOVA and post hoc linear contrasts were used to evaluate the effects of osteoarthritis, breed, and sex on the BMD value.

Results—At necropsy, osteoarthritis was detected in 14 hip joints in 9 dogs; all lesions included early cartilage fibrillation. After adjusting for breed and sex, eBMD in subchondral ROIs 8 and 12 (adjacent to the fovea) were 8% and 6% higher, respectively, in osteoarthritis-affected dogs, compared with unaffected dogs; in the nonsubchondral ROIs, eBMD was 10% higher in osteoarthritis-affected dogs.

Conclusions and Clinical Relevance—Compared with findings in unaffected dogs, increased eBMD in hip joints of dogs with early osteoarthritis supports a strong relationship between the subchondral and epiphyseal regions and articular cartilage in the pathogenesis and progression of osteoarthritis.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To develop an IM xenograft model of canine osteosarcoma in mice for the purpose of evaluating effects of radiation therapy on tumors.

Animals—27 athymic nude mice.

Procedures—Mice were randomly assigned to 1 of 3 groups of 9 mice each: no treatment (control group), radiation at 10 Gy, or radiation at 15 Gy. Each mouse received 5 × 105 highly metastasizing parent osteosarcoma cells injected into the left gastrocnemius muscle. Maximum tumor diameter was determined with a metric circles template to generate a tumor growth curve. Conscious mice were restrained in customized plastic jigs allowing local tumor irradiation. The behavior and development of the tumor xenograft were assessed via evaluations of the interval required for tumor-bearing limbs to reach diameters of 8 and 13 mm, extent of tumor vasculature, histomorphology of tumors, degree of tumor necrosis, and existence of pulmonary metastasis and clinical disease in affected mice.

Results—Tumor-bearing limbs grew to a diameter of 8 mm (0.2-g tumor mass) in a mean ± SEM interval of 7.0 ± 0.2 days in all mice. Interval to grow from 8 to 13 mm was significantly prolonged for both radiation therapy groups, compared with that of the control group. Histologic evaluation revealed the induced tumors were highly vascular and had characteristics consistent with those of osteosarcoma. Pulmonary metastasis was not detected, and there was no significant difference in percentage of tumor necrosis between groups.

Conclusions and Clinical Relevance—A reliable, repeatable, and easily produced IM xenograft model was developed for in vivo assessment of canine osteosarcoma.

Full access
in American Journal of Veterinary Research