SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model

Our plain-English summary of SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model, by T.T. Van, M. Hanibuchi, H. Goto, et al (Respirology, 2012).

The study

• Authors: T.T. Van, M. Hanibuchi, H. Goto, T. Kuramoto, S. Yukishige, S. Kakiuchi, S. Sato, S. Sakaguchi, T. Dat le, Y. Nishioka, S. Akiyama, S. Sone
• Journal: Respirology
• Published: 2012;17(6):984-90
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background And Objective: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the mesothelium with high chemotherapeutic resistance. In this study, the preclinical therapeutic activity of the multiple tyrosine kinase inhibitor, SU6668, against MPM was examined.

Methods: Two human MPM cell lines with different pro-angiogenic cytokine expression, Y-MESO-14 cells that express high levels of vascular endothelial growth factor (VEGF) and MSTO-211H cells that express high levels of basic fibroblast growth factor (bFGF), were orthotopically inoculated into the thoracic cavities of mice with severe combined immunodeficiency. The mice with MPM were treated or not treated with SU6668 (200 mg/kg/day).

Results: SU6668 abrogated the proliferation of endothelial cells stimulated by VEGF or bFGF, but did not directly affect the growth of human MPM cells in vitro. In this orthotopic implantation model, treatment with SU6668 effectively reduced tumour weight and pleural effusion volumes, in association with inhibition of the growth of tumour vasculature. More importantly, treatment with SU6668 significantly prolonged survival time in mice with MPM.

Conclusions: These findings suggest that SU6668 has a promising therapeutic effect on the progression of MPM in vivo through its anti-angiogenic effects.

© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.

In plain English

This laboratory study tested an experimental drug, SU6668, against human malignant pleural mesothelioma. It did not study asbestos exposure. The authors used two human mesothelioma cell lines. Y-MESO-14 made high levels of VEGF, a signal that drives blood-vessel growth. MSTO-211H made high levels of bFGF, another such signal. In laboratory dishes, SU6668 blocked the growth of human blood-vessel lining cells stimulated by VEGF or bFGF, but it did not stop the mesothelioma cells themselves from growing. The cells were then injected into the chest cavities of male mice with severe combined immunodeficiency, meaning their immune systems were severely weakened. From day 7, the mice received SU6668 (200 mg/kg/day) or an inactive liquid by mouth. With both cell lines, treated mice had lighter chest tumours, less pleural fluid and fewer tumour blood vessels. Treated tumours also had fewer dividing cells. Two weeks of treatment lengthened survival compared with mice given the inactive liquid, and four weeks lengthened it further (p less than 0.05). The authors concluded that SU6668 inhibited mesothelioma progression in mice by inhibiting blood-vessel growth.

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) and animal experiment using an orthotopic implantation model, in which human mesothelioma cells were placed in the chest cavity of mice
• Who was studied: Male severe combined immunodeficient (SCID) mice aged 6 to 7 weeks, obtained from CLEA Japan, with ethics approval from Tokushima University. They were injected with one of two human malignant pleural mesothelioma cell lines, Y-MESO-14 or MSTO-211H. Human umbilical vein endothelial cells were used in the dish experiments. The number of mice per group is not stated.
• Exposure: No asbestos exposure was studied. The exposure was the drug SU6668, a multiple tyrosine kinase inhibitor, given orally at 200 mg/kg/day once a day from day 7 after tumour inoculation, compared with vehicle (inactive liquid). Treatment lasted 2 weeks (days 7 to 20) or 4 weeks (days 7 to 34) in the survival experiments.
• Main results:
  • Of the two cell lines, Y-MESO-14 produced relatively high levels of VEGF and MSTO-211H produced significantly higher levels of bFGF.
  • In human umbilical vein endothelial cells, SU6668 inhibited growth stimulated by VEGF or bFGF, with IC50 values of 2.99 and 7.86 respectively. The units are printed as 'mmol/L'; the micro sign appears to have been lost in conversion.
  • SU6668 did not inhibit the growth of the mesothelioma cells themselves in the dish.
  • In mice with Y-MESO-14 tumours, SU6668 significantly reduced thoracic tumour weights and pleural effusion volumes compared with vehicle.
  • Similar effects on tumours and effusions were seen in mice with MSTO-211H tumours.
  • The number of blood vessels inside the tumours was lower in SU6668-treated tumours from both cell lines.
  • SU6668 significantly reduced tumour cell proliferation in the mice, measured by BrdU staining.
  • Two weeks of SU6668 treatment prolonged survival of mice bearing either tumour type (P less than 0.05 compared with vehicle, log-rank test).
  • Four weeks of treatment further increased survival compared with 2-week treatment (P less than 0.05 compared with both the vehicle group and the 2-week group).
  • The survival differences were statistically significant by the log-rank test.
• The authors' conclusion: The authors concluded that SU6668 inhibited the progression of malignant pleural mesothelioma in mice by inhibiting angiogenesis (blood-vessel growth), and that this provides a rationale for developing multiple tyrosine kinase inhibitors as a therapeutic strategy for patients.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Tyrosine Kinase Inhibitor, Pleural Mesothelioma, Neoplasm, Mesothelium, Cytokine, Fibroblast, Pleural Effusion.

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