Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model.

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Mol Cancer Ther. 2008 Mar;7(3):638-47.
Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model.
Laquente B, Lacasa C, Ginestà MM, Casanovas O, Figueras A, Galán M, Ribas IG, Germà JR, Capellà G, Viñals F.
Laboratori
de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital
Duran i Reynals, L'Hospitalet de Llobregat, Spain.
Gemcitabine
shows a marked antitumor effect as a result of its cytotoxic action
toward proliferative cells. In this article, we aim to investigate the
potential antitumor and antiangiogenic effect of gemcitabine following
a metronomic schedule that involves the regular administration of
cytotoxic drugs at doses lower than standard treatment. In vitro
results showed that human endothelial cells are more sensitive to
gemcitabine (IC(50) 3 nmol/L) than pancreatic tumor cells (IC(50) 20
nmol/L). For in vivo studies, we used an orthotopic implantation model
of human pancreatic carcinoma in nude mice.
Gemcitabine was
administered i.p. following a low-dose schedule (1 mg/kg/d for a month)
and compared with the conventional schedule (100 mg/kg days 0, 3, 6,
and 9 postimplantation). Metronomic treatment effect on established
tumor was equivalent to standard administration. The measure of CD31
endothelial marked area allowed us to show an in vivo antiangiogenic
effect of this drug that was further enhanced by using metronomic
administration. This effect correlated with an induction of
thrombospondin-1, a natural inhibitor of angiogenesis.
Our results
allow us to hypothesize that, in addition to a direct antiproliferative
or cytotoxic antiendothelial cell effect, a secondary effect involving
thrombospondin-1 induction might provide an explanation for the
specificity of the effects of metronomic gemcitabine treatment.