title: Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy.
abstract: Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells.
authors.affiliation: Cancer Biology Proteomics Group, Postgraduate Medical Institute, University of Hull, Hull, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Murray
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Little
authors.forename: Paul
authors.initials: P
authors.lastname: Stanley
authors.forename: Anthony
authors.initials: A
authors.lastname: Maraveyas
authors.forename: Lynn
authors.initials: L
authors.lastname: Cawkwell
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001557:Benzenesulfonates / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects*; D005047:Etoposide / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D017239:Paclitaxel / Q000008:administration & dosage; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage*; D000077157:Sorafenib; D000077204:Temozolomide
chemical_list: D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D005047:Etoposide; D003606:Dacarbazine; D000077157:Sorafenib; D017239:Paclitaxel; D000077204:Temozolomide