Abstract
BackgroundHistiocytic sarcoma is a rare disorder in humans, however it is seen with appreciable frequency in certain breeds of dogs, such as Bernese mountain dog. The purpose of this study was to fully characterize a novel canine histiocytic sarcoma cell line, and utilize it as a tool to screen for potential therapeutic drugs.MethodsThe histiocytic sarcoma cell line was characterized by expression of cellular markers as determined by immunohistochemistry and flow cytometry techniques. The neoplastic cells were also evaluated for their capability of phagocytizing beads particles, and their potential to grow as xenograft in an immunodeficient mouse. We investigated the in vitro cytotoxic activity of a panel of thirteen compounds using the MTS proliferation assay. Inhibitory effects of different drugs were compared using one-way ANOVA, and multiple means were compared using Tukey’s test.ResultsNeoplastic cells expressed CD11c, CD14, CD18, CD45, CD172a, CD204, MHC I, and vimentin. Expression of MHC II was upregulated after exposure to LPS. Furthermore, the established cell line clearly demonstrated phagocytic activity similar to positive controls of macrophage cell line. The xenograft mouse developed a palpable subcutaneous soft tissue mass after 29 days of inoculation, which histologically resembled the primary neoplasm. Dasatinib, a tyrosine kinase pan-inhibitor, significantly inhibited the growth of the cells in vitro within a clinically achievable and tolerable plasma concentration. The inhibitory response to dasatinib was augmented when combined with doxorubicin.ConclusionsIn the present study we demonstrated that a novel canine histiocytic sarcoma cell line presents a valuable tool to evaluate novel treatment approaches. The neoplastic cell line favorably responded to dasatinib, which represents a promising anticancer strategy for the treatment of this malignancy in dogs and similar disorders in humans.
Highlights
Histiocytic sarcoma is a rare disorder in humans, it is seen with appreciable frequency in certain breeds of dogs, such as Bernese mountain dog
Characteristics of BD cell line Neoplastic cells in culture grew satisfactorily in 10% fetal bovine serum (FBS) without the addition of specific growth factors with the vast majority of the population growing as adherent and non-clustering cells
Exploring synergistic combinations of drugs We assessed the resulting cytostatic effect caused by increasing concentrations of dasatinib combined to doxorubicin at a fixed concentration close to the correspondent cell line’s IC50
Summary
Histiocytic sarcoma is a rare disorder in humans, it is seen with appreciable frequency in certain breeds of dogs, such as Bernese mountain dog. HS accounts for less than 1% of all hematopoietic neoplasms [1, 2], affects all ages, but predominately adults, and involves lymph nodes and/or a variety of extranodal organs including skin, bone marrow, spleen, the gastrointestinal tract and the central nervous system [3, 4]. This malignancy is often approached with a combination of various modalities of treatment, including multi-drug chemotherapeutic. Additional alternatives of treatment have been investigated on small cohorts of dogs, including delivery of the human MHC non-restricted T-cell line TALL-104, frameless stereotactic radiosurgery, and chemotherapy using either paclitaxel or pegylatedliposomal doxorubicin; none has shown promising results [20,21,22,23,24]
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