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Combination of Temsirolimus and tyrosine kinase inhibitors in renal carcinoma and endothelial cell lines

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Abstract

Purpose

Multitargeted tyrosine kinase inhibitors (TKIs) (such as Sunitinib and Sorafenib) and mTOR inhibitors (such as Temsirolimus) are effective in treating metastatic clear-cell renal cell carcinoma (CCRCC), by acting on different pathways in both tumour and endothelial cells. A study of their combined effect could be of major interest.

Methods

We studied endothelial and CCRCC cell lines treated with Sunitinib, Sorafenib, Temsirolimus and 2 drug combinations: Sunitinib–Temsirolimus and Sorafenib–Temsirolimus. We studied inhibition of proliferation with an MTT assay under normoxia and hypoxia, VEGF expression by quantitative RT–PCR and ELISA, and angiogenesis with a Matrigel assay.

Results

TKIs and Temsirolimus inhibited proliferation of endothelial and tumour cell lines and inhibited angiogenesis. Anti-proliferative effects were more significant on cell lines with VHL gene inactivation and under hypoxic conditions. VEGF expression was induced by TKIs, but inhibited by Temsirolimus. The Sunitinib/Temsirolimus combination had synergistic or additive effects on the proliferation of tumour and endothelial cell lines. The Sorafenib–Temsirolimus combination had additive effects on the proliferation of most tumour cell lines, but not endothelial cell lines. Both combinations had additive effects on the inhibition of angiogenesis.

Conclusion

In our model, Sunitinib, Sorafenib and Temsirolimus had anti-tumour and anti-angiogenic effects. The combinations of Sunitinib or Sorafenib with Temsirolimus had additive or synergistic effects on the inhibition of tumour and endothelial cell proliferation, and on the inhibition of angiogenesis. This work could lead to new trials with lower-dose combinations to prevent side effects and enhance efficacy.

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Conflict of interest

Jean-Jacques Patard is consultant for Pfizer, Bayer, Wyeth, Wilex. Other authors have no relevant conflict of interest.

Author information

Authors and Affiliations

  1. CNRS/UMR 6061, Université de Rennes 1, IFR140, 2 av du Professeur Léon Bernard, 35043, Rennes, France

    Bénédicte Martin, Jean-Jacques Patard, Florence Jouan, Gaëlla Boulanger, Cécile Vigneau & Nathalie Rioux-Leclercq

  2. Centre Eugène Marquis, Département d’Oncologie Médicale, Rennes, France

    Julien Edeline

  3. CNRS/UMR 6061, Université de Rennes 1, IFR140, Rennes, France

    Julien Edeline

  4. CHU Pontchaillou, Service de Pharmacologie, 2 Rue Henri Le Guilloux, 35043, Rennes, France

    Emmanuel Oger

  5. CHU Pontchaillou, Laboratoire de Biochimie, 2 Rue Henri Le Guilloux, 35043, Rennes, France

    Sélim Zerrouki

  6. CHU Pontchaillou, Service de Néphrologie, Rennes, France

    Cécile Vigneau

  7. CHU Pontchaillou, Service d’Anatomie et Cytologie Pathologiques, Rennes, France

    Nathalie Rioux-Leclercq

  8. CHU Pontchaillou, Service d’Urologie, Rennes, France

    Jean-Jacques Patard

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  1. Bénédicte Martin
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  2. Julien Edeline
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  3. Jean-Jacques Patard
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  4. Emmanuel Oger
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  5. Florence Jouan
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  6. Gaëlla Boulanger
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  7. Sélim Zerrouki
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  8. Cécile Vigneau
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  9. Nathalie Rioux-Leclercq
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Corresponding author

Correspondence to Julien Edeline.

Additional information

B. Martin and J. Edeline contributed equally to this work.

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Martin, B., Edeline, J., Patard, JJ. et al. Combination of Temsirolimus and tyrosine kinase inhibitors in renal carcinoma and endothelial cell lines. J Cancer Res Clin Oncol 138, 907–916 (2012). https://doi.org/10.1007/s00432-012-1162-x

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  • DOI: https://doi.org/10.1007/s00432-012-1162-x

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