Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib.

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Br J Cancer. 2008 May 20;98(10):1619-29. Epub 2008 Apr 29.
Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib.
Bocci G, Falcone A, Fioravanti A, Orlandi P, Di Paolo A, Fanelli G, Viacava P, Naccarato AG, Kerbel RS, Danesi R, Del Tacca M, Allegrini G.
Division
of Pharmacology and Chemotherapy, Department of Internal Medicine,
University of Pisa, Pisa, Italy.

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.