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

• Published in: Journal of cancer research and clinical oncology 2012-06, Vol.138 (6), p.907-916
• Main Authors: Martin, Bénédicte, Edeline, Julien, Patard, Jean-Jacques, Oger, Emmanuel, Jouan, Florence, Boulanger, Gaëlla, Zerrouki, Sélim, Vigneau, Cécile, Rioux-Leclercq, Nathalie
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Benzenesulfonates - administration & dosage; Biological and medical sciences; Cancer; Cancer Research; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Synergism; Drug Therapy, Combination - methods; Hematology; Human health and pathology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; Indoles - administration & dosage; Inhibitor drugs; Internal Medicine; Kidney Neoplasms - blood supply; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidneys; Life Sciences; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Nephrology. Urinary tract diseases; Niacinamide - analogs & derivatives; Oncology; Original Paper; Pharmaceutical sciences; Pharmacology. Drug treatments; Phenylurea Compounds; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyridines - administration & dosage; Pyrroles - administration & dosage; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Tumors of the urinary system; Urology and Nephrology
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-012-1162-x

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.