Abstract:
: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.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Laquente B,Lacasa C,Ginestà MM,Casanovas O,Figueras A,Galán M,Ribas IG,Germà JR,Capellà G,Viñals Fdoi
10.1158/1535-7163.MCT-07-2122subject
Has Abstractpub_date
2008-03-01 00:00:00pages
638-47issue
3eissn
1535-7163issn
1538-8514pii
7/3/638journal_volume
7pub_type
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