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.

Incidence of Sterile Hemorrhagic Cystitis in Dogs Treated with Cyclophosphamide and Low-Dose Furosemide.

Cyclophosphamide is a commonly used chemotherapy in the treatment of lymphoma. It can cause sterile hemorrhagic cystitis (SHC), and furosemide is used to decrease the incidence of SHC. The aim of this study is to evaluate the incidence of SHC in dogs treated with a bolus maximum tolerated dose of oral cyclophosphamide and oral furosemide at a dose of 1 mg/kg. Medical records were reviewed to determine the incidence of SHC, dose and number of oral cyclophosphamide treatments, and the dose of furosemide. Other side effects from cyclophosphamide were also recorded. Eighty-one client-owned dogs that received a single oral maximum tolerated dose of cyclophosphamide concurrent with oral furosemide as part of a chemotherapy protocol for lymphoma were included in the study. A total of 252 doses of cyclophosphamide were administered to 81 dogs. The median dose of cyclophosphamide was 239.3 mg/m2. The median dose of furosemide was 1.08 mg/kg. SHC was suspected in 2 dogs (2.46%). Concurrent use of furosemide at a dose of 1 mg/kg with cyclophosphamide yields a similar incidence of SHC than using a higher dose of furosemide as previously reported.

A clinically relevant combination treatment with doxorubicin and cyclophosphamide does not induce hepatotoxicity in C57BL/6J mice.

BACKGROUND AND AIM: Chronic exposure to chemotherapeutics can lead to severe adverse events including hepatotoxicity. A combination chemotherapy regimen of doxorubicin (DOX) and cyclophosphamide (CPS) is employed in treatment of several cancers such as leukemia, lymphoma, and breast cancer. It is not well understood whether a combination therapy of DOX and CPS can induce hepatotoxicity. We therefore sought to determine whether co-administration of DOX and CPS at their clinically relevant doses and frequency results in hepatotoxicity. METHODS: Male C57BL/6J mice received one intraperitoneal injection of saline or DOX-2mg /kg and CPS-50mg/kg once a week for 4 weeks. After the treatment period, liver histology and various serum biomarkers of hepatotoxicity were assessed. RESULTS: Co-treatment of DOX and CPS did not alter the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, globulin, or total protein. Similarly, co-administration of DOX and CPS did not result in a noticeable change in liver histology. However, it was notable that the concomitant treatment with DOX and CPS resulted in a significant increase in serum levels of aspartate aminotransferase (AST). Elevated serum AST levels were also associated with increased serum creatinine kinase (CK) levels, suggesting that the elevated serum AST levels are likely due to muscle injury following the co-administration of DOX and CPS. CONCLUSION: Taken together, our results, for the first time, suggest that co-administration of DOX and CPS, at their clinically relevant doses and frequency does not induce a significant hepatotoxicity in the mice.

Canine myxosarcomas, a retrospective analysis of 32 dogs (2003-2018).

BACKGROUND: Myxosarcomas are known to be classified as soft tissue sarcomas. However, there is limited clinical characterization pertaining specifically to canine cutaneous myxosarcomas in the literature. The objective of this study is to evaluate the local recurrence rate, metastatic rate and prognosis of canine myxosarcoma. RESULTS: A total of 32 dogs diagnosed with myxosarcoma via histopathology were included in this retrospective study. All dogs had surgical resection. No adjunct treatments were performed in 9 dogs, while 22 dogs also received either radiation therapy or chemotherapy, or a combination of both. One dog received only NSAID after surgery. Overall median survival time (MST) was 730 days (range 20-2345 days). The MST of dogs with a tumor mitotic count < 10/10 HPF was 1393 days (range 20-2345 days). The dogs with a tumor mitotic count of 10 or greater/10 HPF had a MST of 433 days (range 169-831 days). There was no significant difference of MST among different treatment modalities. Local recurrence was noted in 13 cases (40.6%) and the median time to recurrence was 115.5 days (range 50-1610 days). The median time to local recurrence in dogs with mitotic count of < 10/10 HPF was 339 days (range 68-1610 days) and in dogs with mitotic count of 10 or greater/10 HPF was 119 days (range 50-378). Metastasis to local lymph node or lung was noted in 8 cases (25%) with median time to metastasis of 158.5 days (range 0-643 days). CONCLUSIONS: Based on the results of this retrospective study, myxosarcoma may have a higher local recurrence rate and risk of metastasis to the local lymph nodes compared to other soft tissue sarcomas.

Tonsillar plasmacytoma in a dog.

A 10-year-old greyhound dog was presented because of an incidental finding of a tonsillar mass. Excisional surgical biopsy was performed and the dog was diagnosed with an incompletely resected plasma cell tumor. Adjuvant therapy was declined. One year later there was no local recurrence or distant metastasis of the mass or clinical signs associated with the tonsillar plasmacytoma.

Plasmacytome tonsillaire chez un chien. Un chien Greyhound âgé de 10 ans a été présenté en raison de la découverte fortuite d'une masse tonsillaire. Une biopsie par excision chirurgicale a été réalisée et le chien a été diagnostiqué avec une tumeur à plasmocytes avec résection incomplète. Le traitement avec adjuvant a été refusé. Une année plus tard, il n'y avait aucune récurrence locale ou de métastase distante de la masse ou de signes cliniques associés au plasmacytome tonsillaire.(Traduit par Isabelle Vallières).

Enhancement of antibody production against rabies virus by uridine 5'-triphosphate in mice.

Extracellular nucleotides such as adenosine 5'-triphospate (ATP) and uridine 5'-triphosphate (UTP) interact with P2 purinergic receptors on the surface of phagocytic cells and induce various physiological reactions. In this study, the production of antibody in mice immunized with an inactivated rabies vaccine containing these nucleotides was investigated. Injection of inactivated rabies vaccine with UTP, but not with ATP, induced significantly higher serum antibody production in mice. The enhancement of antibody production by UTP was inhibited by an anti-P2Y4 receptor antibody. In an air pouch experiment, UTP treatment increased the number of monocytes and macrophages infiltrating the pouch and up-regulated the gene expression of IL-4 and IL-13 in the regional lymph nodes. These results suggested that UTP admixed with rabies vaccine activates Th2 cells and induces a humoral immune response. Furthermore, the survival rate of mice immunized with a rabies vaccine admixed with UTP before rabies virus challenge was slightly higher than that of control mice. In conclusion, UTP can act as a vaccine adjuvant to enhance antibody production against the rabies virus in mice.