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Research Articles: Therapeutics, Targets, and Development

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

¹ Laboratori de Recerca Translacional and ² Servei d'Oncologia Mèdica, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals; ³ Department Ciències Fisiològiques II, Universitat de Barcelona-IDIBELL, L'Hospitalet de Llobregat, Spain; and ⁴ Internacional Lilly S.A., Madrid, Spain

Requests for reprints: Francesc Viñals, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Gran Via s/n km 2,7, 08907 L'Hospitalet de Llobregat, Spain. E-mail: fvinyals{at}ico.scs.es or Gabriel Capellà, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Gran Via s/n km 2,7, 08907 L'Hospitalet de Llobregat, Spain. E-mail: gcapella{at}ico.scs.es

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 (IC₅₀ 3 nmol/L) than pancreatic tumor cells (IC₅₀ 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. [Mol Cancer Ther 2008;7(3):638–47]

Grant support: Ministerio de Educación y Ciencia [Programa Ramón y Cajal BFI2001-2987 and SAF2004-01350 (F. Viñals) and AGL2004-07579-04 (G. Capellà)] and Lilly Spain.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ http://calculators.stat.ucla.edu/powercalc

Received 9/20/07; revised 11/12/07; accepted 11/27/07.