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- Title
Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib.
- Authors
Bocci, G.; Falcone, A.; Fioravanti, A.; Orlandi, P.; Di Paolo, A.; Fanelli, G.; Viacava, P.; Naccarato, A. G.; Kerbel, R. S.; Danesi, R.; Del Tacca, M.; Allegrini, G.
- Abstract
Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice.
- Subjects
COLON cancer treatment; COLON cancer; DRUG therapy; APOPTOSIS; TOXICITY testing; ANIMAL experimentation; ANTINEOPLASTIC agents; CAMPTOTHECIN; CELL physiology; COLON tumors; COMPARATIVE studies; ENZYME-linked immunosorbent assay; GENES; GLYCOPROTEINS; HETEROCYCLIC compounds; IMMUNOENZYME technique; IMMUNOHISTOCHEMISTRY; RESEARCH methodology; MEDICAL cooperation; MICE; MICROCIRCULATION; NEOVASCULARIZATION inhibitors; RECTUM tumors; RESEARCH; XENOGRAFTS; EVALUATION research; VASCULAR endothelial growth factors; INDOLE compounds; PHARMACODYNAMICS
- Publication
British Journal of Cancer, 2008, Vol 98, Issue 10, p1619
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/sj.bjc.6604352