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Neoplasia. 2011 Mar;13(3):217-29.

Irinotecan synergistically enhances the antiproliferative and proapoptotic effects of axitinib in vitro and improves its anticancer activity in vivo.

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  • 1Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa, Italy.

Abstract

AIMS:

To demonstrate the synergistic antiproliferative and proapoptotic activity of irinotecan and axitinib in vitro and the improvement of the in vivo effects on angiogenesis and pancreatic cancer.

METHODS:

Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells and pancreas cancer (MIAPaCa-2, Capan-1) cell lines exposed to SN-38, the active metabolite of irinotecan, axitinib, or their simultaneous combination for 72 hours. ERK1/2 and Akt phosphorylation, the vascular endothelial growth factor (VEGF), VEGF receptor-2, and thrombospondin-1 (TSP-1) concentration were measured by ELISAs. ATP7A and ABCG2 gene expression was performed with real-time polymerase chain reaction and SN-38 intracellular concentrations were measured by high-performance liquid chromatography. Capan-1 xenografts in nude mice were treated with irinotecan and axitinib alone or in simultaneous combination.

RESULTS:

A strong synergistic effect on antiproliferative and proapoptotic activity was found with the axitinib/SN-38 combination on endothelial and cancer cells. ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the combined drugs in all the cell lines. Axitinib and SN-38 combined treatment greatly inhibited the expression of the ATP7A and ABCG2 genes in endothelial and cancer cells, increasing the SN-38 intracellular concentration. Moreover, TSP-1 secretion was increased in cells treated with both drugs, whereas VEGFR-2 levels significantly decreased. In vivo administration of the simultaneous combination determined an almost complete regression of tumors and tumor neovascularization.

CONCLUSIONS:

In vitro results show the highly synergistic properties of simultaneous combination of irinotecan and axitinib on endothelial and pancreas cancer cells, suggesting a possible translation of this schedule into the clinics.

PMID:
21390185
[PubMed - indexed for MEDLINE]
PMCID:
PMC3050865
Free PMC Article

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