An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells.

Introduction: Osteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells. Methods: Canine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC5, IC10, IC20, and IC50 were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC5, IC10, IC20, and IC50 concentrations. After 72 hours, cell viability was assessed by CellTiter Glo. Results and discussion: Zoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action.

Evaluation of zoledronate for the treatment of canine stage III osteosarcoma: A phase II study.

BACKGROUND: Greater than 90% of dogs with appendicular osteosarcoma will develop pulmonary metastasis despite the standard of care. Available treatments have limited efficacy for stage III disease. Zoledronate, a bisphosphonate, induces apoptosis of canine osteosarcoma cells and appears to modulate the tumour microenvironment. OBJECTIVES: This prospective, single institutional phase IIa trial investigated the use of single agent zoledronate in dogs with pulmonary metastases from osteosarcoma. METHODS: Zoledronate was administered once monthly, and thoracic radiographs were used to assess response. RESULTS: Eleven dogs were enrolled. Stable disease was achieved in two of eight dogs available for response assessment. The median progression-free survival was 28 days (range: 4-93 days). The median stage III-specific survival time was 92 days. Adverse events were reported in four dogs; two dogs developed grade III or higher toxicities. Notable adverse events included conjunctivitis, fever, hypocalcaemia, and hypophosphatemia. CONCLUSIONS: Zoledronate appears to have limited efficacy as a single agent for stage III osteosarcoma and may be associated with unexpected toxicity in this population. This clinical trial was registered on the AVMA Animal Health Studies Database (AAHSD004396).

Partial parotid sialoadenectomy in a horse with parotid ductal carcinoma: Surgical description and case report.

OBJECTIVES: To describe the surgical findings, histopathological features, and long-term outcome for a horse with parotid salivary carcinoma. STUDY DESIGN: Case report ANIMALS: Twelve year old American Quarter Horse gelding. METHODS: The gelding was presented for a 10 × 10 cm swelling below the base of the right ear. Ultrasonographic examination revealed a mass involving the right parotid salivary gland. Incisional biopsy was consistent with parotid carcinoma. The tumor was marginally excised. The lateral wall of the guttural pouch was excised with the mass and was reconstructed with a porcine small intestinal submucosal (SIS) sheet. Cisplatin beads were implanted in the wound bed prior to closure. Firocoxib (0.1 mg/kg orally, daily, every 24 h) treatment was initiated. RESULTS: Postoperative complications included right-sided facial nerve paralysis, difficulty with deglutition of fibrous feeds, and surgical site dehiscence. Wound healing was achieved by second intention. Partial improvement in nerve function was observed within the first 6 months. At 12 months postparotidectomy, no sign of tumor reoccurrence or metastatic disease was present, and the gelding returned to work. CONCLUSION: Partial parotid sialoadenectomy was performed with a favorable long-term outcome. Regional anatomic knowledge is crucial.

Substitution of mitoxantrone for doxorubicin in a multidrug chemotherapeutic protocol for first-line treatment of dogs with multicentric intermediate- to large-cell lymphoma.

OBJECTIVE To evaluate effects of substituting mitoxantrone for doxorubicin in a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapeutic protocol for first-line treatment of dogs with multicentric intermediate- to large-cell lymphoma. DESIGN Retrospective cohort study. ANIMALS 44 dogs treated with cyclophosphamide, mitoxantrone, vincristine, and prednisone (CMOP) and 51 dogs treated with CHOP at 12 referral institutions. PROCEDURES Medical records were reviewed to determine response to treatment, progression-free survival time, and overall survival time. For dogs treated with CMOP, adverse events were also recorded. RESULTS All 44 (100%) dogs treated with CMOP and 37 of 38 (97.4%) dogs treated with CHOP had a complete or partial response. Median progression-free survival time for dogs treated with CMOP was 165 days (95% confidence interval [CI], 143 to 187 days), and median overall survival time was 234 days (95% CI, 165 to 303 days). For dogs treated with CHOP, median progression-free survival time was 208 days (95% CI, 122 to 294 days), and median overall survival time was 348 days (95% CI, 287 to 409 days). Progression-free and overall survival times were not significantly different between groups. Overall, 9 of the 44 (20%) dogs treated with CMOP had adverse events likely or probably related to mitoxantrone, but all of these adverse events were mild. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that mitoxantrone may be a reasonable substitution in a CHOP protocol for treatment of dogs with multicentric intermediate- to large-cell lymphoma when doxorubicin is contraindicated.