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Published on: March 18, 2014
Effects of trastuzumab emtansine on canine osteosarcoma cells
Kosei Sakai1, Daiki Kato2, Junka Yoshinaka3
1Laboratory of Small Animal Internal Medicine 1, School of Veterinary Medicine, Kitasato University, Aomori, Japan.
Abstract:
Human epidermal growth factor receptor 2 (HER2) is a known therapeutic target in canine osteosarcoma (OSA); however, the efficacy of anti-HER2 antibody drugs remains unclear. This study aimed to investigate the effects of the anti-HER2 antibody drugs including trastuzumab and trastuzumab emtansine (T-DM1) on canine OSA cell lines in vitro and in vivo. Four canine OSA cell lines (HMPOS, POS, OOS, and HOS) were used. Western blotting revealed HER2 protein expression in all the cell lines. Although water-soluble tetrazolium salt assays showed growth inhibitory activity of trastuzumab and T-DM1 against all the cell lines in vitro, the activity of T-DM1 was significantly stronger than that of trastuzumab. Flow cytometric analysis of the canine OSA cell line (HMPOS) revealed that T-DM1, but not trastuzumab, significantly increased the sub-G1 phase fraction in cell cycle analyses and the percentage of early and late apoptotic cells in annexin V apoptotic assays. For in vivo experiments, canine OSA cells (HMPOS) were subcutaneously injected into nude mice. Six days after inoculation, trastuzumab, T-DM1, or the vehicle control was administered intraperitoneally once per week. Survival until the tumor volume in the canine OSA-engrafted mice reached mean final tumor volume in the T-DM1 group was significantly longer in the T-DM1 group, but not in the trastuzumab group, compared to the vehicle control group. These findings indicated that T-DM1 exerts antitumor effects on canine OSA cells in vitro and in vivo, possibly by inducing apoptosis due to DM1.
Insights
Trastuzumab emtansine (T-DM1) shows significant antitumor effects against canine osteosarcoma (OSA) cells in vitro and in vivo. T-DM1 demonstrated stronger growth inhibition and induced apoptosis, leading to improved survival in canine OSA models.
Area of Science:
- Veterinary Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Canine osteosarcoma (OSA) is an aggressive bone cancer.
- Human epidermal growth factor receptor 2 (HER2) is a potential therapeutic target in canine OSA.
- The clinical efficacy of anti-HER2 antibody drugs in canine OSA is not well-established.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of trastuzumab and trastuzumab emtansine (T-DM1) targeting HER2 in canine osteosarcoma.
- To compare the anti-cancer activity of T-DM1 with trastuzumab in canine OSA models.
Main Methods:
- Utilized four canine osteosarcoma (OSA) cell lines (HMPOS, POS, OOS, HOS) for in vitro studies.
- Assessed HER2 protein expression via Western blotting.
- Evaluated drug efficacy using water-soluble tetrazolium salt assays, cell cycle analysis (sub-G1 fraction), and apoptosis assays (Annexin V).
- Conducted in vivo experiments using nude mice xenografted with canine OSA cells (HMPOS), administering trastuzumab, T-DM1, or vehicle control intraperitoneally.
Main Results:
- All tested canine OSA cell lines expressed HER2 protein.
- Both trastuzumab and T-DM1 exhibited in vitro growth inhibitory activity, with T-DM1 showing significantly stronger effects.
- T-DM1 treatment led to increased sub-G1 phase fraction and higher rates of early and late apoptosis in canine OSA cells.
- In vivo, T-DM1 significantly prolonged survival in mice with canine OSA xenografts compared to the vehicle control, whereas trastuzumab did not show a significant survival benefit.
Conclusions:
- Trastuzumab emtansine (T-DM1) demonstrates potent antitumor effects against canine osteosarcoma cells both in vitro and in vivo.
- T-DM1's efficacy is likely mediated through the induction of apoptosis, potentially linked to its payload, DM1.
- These findings support T-DM1 as a promising therapeutic candidate for canine osteosarcoma targeting HER2.
