1. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor.
- Author
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Lane HA, Wood JM, McSheehy PM, Allegrini PR, Boulay A, Brueggen J, Littlewood-Evans A, Maira SM, Martiny-Baron G, Schnell CR, Sini P, and O'Reilly T
- Subjects
- Angiogenesis Inhibitors pharmacokinetics, Animals, Cell Movement drug effects, Cell Proliferation drug effects, Everolimus, Female, Humans, Immunoenzyme Techniques, Magnetic Resonance Imaging, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Phthalazines pharmacokinetics, Protein Kinase Inhibitors pharmacokinetics, Protein Kinases metabolism, Pyridines pharmacokinetics, Rats, Rats, Inbred BN, Rats, Inbred WF, Receptor, TIE-2 metabolism, Receptors, Vascular Endothelial Growth Factor metabolism, Sirolimus pharmacokinetics, Sirolimus pharmacology, TOR Serine-Threonine Kinases, Tissue Distribution, Transplantation, Heterologous, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inhibitors pharmacology, Neoplasms, Experimental blood supply, Neovascularization, Pathologic drug therapy, Phthalazines pharmacology, Protein Kinase Inhibitors pharmacology, Protein Kinases chemistry, Pyridines pharmacology, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Sirolimus analogs & derivatives
- Abstract
Purpose: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK)., Experimental Design: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK., Results: RAD001 inhibited proliferation in vitro (IC50 values<1 nmol/L to >1 micromol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values>10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001., Conclusions: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.
- Published
- 2009
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