title: Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib.
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.
authors.affiliation: Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy. g.bocci@med.unipi.it
authors.forename: G
authors.initials: G
authors.lastname: Bocci
authors.forename: A
authors.initials: A
authors.lastname: Falcone
authors.forename: A
authors.initials: A
authors.lastname: Fioravanti
authors.forename: P
authors.initials: P
authors.lastname: Orlandi
authors.forename: A
authors.initials: A
authors.lastname: Di Paolo
authors.forename: G
authors.initials: G
authors.lastname: Fanelli
authors.forename: P
authors.initials: P
authors.lastname: Viacava
authors.forename: A G
authors.initials: AG
authors.lastname: Naccarato
authors.forename: R S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
authors.forename: G
authors.initials: G
authors.lastname: Allegrini
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D011758:Pyrroles; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D000077146:Irinotecan; D002166:Camptothecin