Chemosensitivity of three patient-derived primary cultures of canine pericardial mesothelioma by single-agent and combination treatment

Our plain-English summary of Chemosensitivity of three patient-derived primary cultures of canine pericardial mesothelioma by single-agent and combination treatment, by R. Nabeta, A. Kanaya, M. Elbadawy, et al (Frontiers in Veterinary Science, 2023).

The study

• Authors: R. Nabeta, A. Kanaya, M. Elbadawy, T. Usui, T. Furuya, K. Suzuki, T. Uchide
• Journal: Frontiers in Veterinary Science
• Published: 2023;10:1267359
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Canine mesothelioma is a rare malignant tumor that mostly affects body cavities, such as the pericardial and pleural cavities. Chemotherapy plays a crucial role in the treatment of canine mesotheliomas. We aimed to compare the antitumor effects of single-agent and combination chemotherapeutic agents on patient-derived primary cultures of canine pericardial mesothelioma established in this study. We planned to generate xenograft models for future studies.

Material And Methods: Effusion samples were collected from three dogs with histologically diagnosed pericardial mesothelioma and used for primary culture. Cultured cells were characterized by immunostaining for pan-cytokeratin AE1/AE3, vimentin, Wilms' tumor suppressor gene 1 (WT1), and cytokeratin 5 (CK5). To assess the tumorigenic properties of cells in the effusion and generate a xenograft model, the cell suspension was injected into a severe combined immunodeficient (SCID) mouse either subcutaneously (SC) or intraperitoneally (IP). Lastly, chemosensitivity of established primary cultures against four drugs, doxorubicin, vinorelbine, carboplatin, and gemcitabine, by single-agent treatment as well as combination treatment of carboplatin at a fixed concentration, either 10 or 100 μM, and gemcitabine at different concentrations ranging from 0-1000 μM was assessed by cell viability assay.

Results: Primary cultures were successfully generated and characterized by dual positivity for AE1/AE3 and vimentin and positive staining for WT-1 and CK5, confirming the mesothelial origin of the cells. In the xenograft models, SC mouse developed a subcutaneous mass, whereas IP mouse developed multiple intraperitoneal nodules. The masses were histopathologically consistent with mesotheliomas. The chemosensitivity assay revealed that carboplatin had the highest anti-tumor effects among the four tested single-agent treatments. Furthermore, carboplatin at 100 μM combined with gemcitabine at clinically relevant doses demonstrated the augmented anti-tumor effects compared to single-agent treatment.

Discussion And Conclusion: Primary cultures and xenograft models generated in this study could be useful tools for in vitro and in vivo studies of canine mesothelioma. Carboplatin is a highly effective chemotherapeutic agent against canine mesothelioma when used as a sole agent and in combination with gemcitabine.

Copyright © 2023 Nabeta, Kanaya, Elbadawy, Usui, Furuya, Suzuki and Uchide.

In plain English

This laboratory study, from Tokyo University of Agriculture and Technology, used fluid samples taken between 2018 and 2019 from three dogs with pericardial mesothelioma (a cancer of the sac around the heart) confirmed by tissue examination. The article does not discuss asbestos. The authors grew the tumor cells in the lab and confirmed by staining that they were mesothelial cells. They injected cells from one dog into two immune-deficient mice. One mouse developed a mass under the skin after 60 days, and the other developed small nodules in the abdomen; both were consistent with mesothelioma. The authors then tested four cancer drugs on the three cell cultures. At 100 µM, carboplatin reduced cell growth to an average of 20.6% of untreated cells. At concentrations the authors considered clinically relevant, carboplatin was the most effective of the four drugs. Adding gemcitabine to 100 µM carboplatin significantly lowered cell viability in one of the three cultures. In another culture the decrease was not statistically significant. The authors concluded that their results support carboplatin as a first-choice single drug for canine mesothelioma. They said further studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of tumor cell cultures grown from dog patients, with a small mouse xenograft experiment
• Who was studied: Three pet dogs with histologically confirmed pericardial mesothelioma (a Yorkshire Terrier, a Miniature Dachshund and a Miniature Bull Terrier), referred to the Animal Medical Center, Tokyo University of Agriculture and Technology, Japan, in 2018 to 2019. Cells from one dog (case 1) were also injected into two SCID mice.
• Exposure: No asbestos or other fiber exposure was studied. The exposures tested were chemotherapy drugs applied to the cultured cells: doxorubicin, vinorelbine and carboplatin at 0.1, 1, 10 and 100 µM; gemcitabine at 1, 10, 100 and 1000 µM; and carboplatin fixed at 10 or 100 µM combined with gemcitabine at 0 to 1000 µM.
• Main results:
  • The cultured cells stained positive for the mesothelial markers WT1 and CK5, as well as for AE1/AE3 and vimentin
  • The mouse injected under the skin developed a visible mass 60 days after injection
  • The mouse injected into the abdomen developed several small nodules, 1 to 2 mm across, on the membrane lining the abdominal cavity
  • Doxorubicin reduced cell growth to an average of 64.3%, 49.7%, 27.5% and 9.8% of untreated control at 0.1, 1, 10 and 100 µM; this was statistically significant at 10 µM and above in all three cell lines
  • Vinorelbine reduced cell growth to an average of 46.2%, 44.0%, 31.3% and 6.0% of untreated control at 0.1, 1, 10 and 100 µM; this was statistically significant at 1 µM and above in all cell lines
  • Carboplatin reduced cell growth only at 100 µM: averages were 99.0%, 98.0%, 89.0% and 20.6% of untreated control at 0.1, 1, 10 and 100 µM; this was statistically significant at 100 µM in all three lines
  • Gemcitabine effects were inconsistent: two cell lines were sensitive at 1 µM, while the case 3 cell line was resistant even at 1000 µM
  • At concentrations the authors considered clinically relevant, carboplatin was the most effective of the four drugs
  • With carboplatin at 10 µM, adding gemcitabine at clinically relevant concentrations (100 µM or less) gave no added effect
  • Carboplatin at 100 µM combined with gemcitabine at 1 µM or more significantly decreased cell viability in one cell line (case 2) compared with single-agent treatment
  • In the case 3 cell line, the combination tended to decrease cell viability, but this was not statistically significant
• The authors' conclusion: The authors concluded that their results support the historical use of carboplatin as the first-choice single-agent chemotherapy for canine mesothelioma. They also concluded that cultures grown from the dogs' effusions are feasible research tools.
• Limitations the authors state:
  • The authors stated that further preclinical and clinical studies are required to validate the results
  • The authors noted that in the abdominal (IP) mouse model it is difficult to assess tumor development, disease progression and drug response
  • The authors stated that further studies are needed to evaluate the clinical use of the carboplatin-gemcitabine combination in dogs

Topics

Medical terms in this study, explained in our Lexicon: Pericardial Mesothelioma, Mesothelioma, Pericardial, Chemotherapy, Tumor Suppressor Gene, Doxorubicin, Vinorelbine, Carboplatin.

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• Adaptation of a chemosensitivity assay to accurately assess pemetrexed in ex vivo cultures of lung cancer — S.L. Suchy, R.J. Landreneau, et al. (2013)

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