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Cited by 49Angiogenesis and VEGF in CancerPancreatic and Hepatic Oncology ResearchPancreatic function and diabetes

Antiangiogenic versus cytotoxic therapeutic approaches to human pancreas cancer: an experimental study with a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor and gemcitabine

Bocci, Guido, Danesi, Romano, Marangoni, Gabriele, Fioravanti, Anna, Boggi, Ugo, Esposito, Irene, Fasciani, Alessandro, Boschi, Elena +4 more·2004·European Journal of Pharmacology
DOI 10.1016/j.ejphar.2004.07.062
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Abstract

Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem. The pharmacological control of angiogenesis might represent a novel approach to the management of pancreas cancer, since the pathological development of vascular supply is a critical step for tumor growth and may affect its prognosis. In order to test this hypothesis, SU5416 ([3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one]) a selective inhibitor of the vascular endothelial growth factor receptor-2 tyrosine kinase, and gemcitabine (2', 2'-difluorodeoxycytidine) were tested on endothelial (HUVEC) and pancreatic tumor cells (MIA PaCa-2) in vitro and in vivo alone and in simultaneous association. SU5416 inhibited HUVEC cells stimulated to proliferate by vascular endothelial growth factor but not MIA PaCa-2 cells; the drug concentration that decreased cell growth by 50% (IC50) was 0.14 microM. Furthermore, SU5416 reduced the development of microvessels from placental explants (IC50, 0.23 microM). Gemcitabine inhibited the growth of both HUVEC and MIA PaCa-2 cells with an IC50 of 0.08 and 0.1 microM, respectively. A synergistic effect (combination index <1 and dose reduction index >1) on anti-proliferative and pro-apoptotic activity was calculated with the simultaneous combination of the two drugs on endothelial cells. A marked in vivo antitumor effect on MIA PaCa-2 xenografts was observed with SU5416 at a protracted schedules, as well as with gemcitabine; furthermore, the combination between the two drugs resulted in an almost complete suppression of tumor growth and relapse. In conclusion, the present results provide the evidence of an effective anti-endothelial/antitumor activity of protracted administration of SU5416 on human pancreas cancer xenografts, which is comparable with the one obtained by gemcitabine; moreover, the synergistic combination between these drugs on endothelial cells and the promising association in pancreatic cancer xenografts could be used in future studies and translated into the clinical setting.

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Authors
Bocci, G., Danesi, R., Marangoni, G., Fioravanti, A., Boggi, U., Esposito, I., Fasciani, A., Boschi, E., Campani, D., Bevilacqua, G., Mosca, F., & Del Tacca, M.
Affiliations
University of Pisa (IT)
Corresponding author
Danesi, Romano
ORCID
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
2004-09
Volume
498
Issue
1-3
Pages
9-18
ISSN
0014-2999 (ISSN-L)
DOI
10.1016/j.ejphar.2004.07.062
OpenAlex
W2092806449
Cited by
49
References
49
Citations by year
2026: 1 · 2023: 1 · 2020: 2 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 1
FWCI
2.49
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • European Journal of Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
Funders
F. Hoffmann-La Roche
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
pancreatic ductal adenocarcinoma, anti-angiogenic therapy, SU5416, bevacizumab, gemcitabine, combination chemotherapy, drug synergy, endothelial cell proliferation, MIA PaCa-2 cells, tumor xenografts, tumor angiogenesis, apoptosis
MeSH terms
Gemcitabine, Animals, Antimetabolites, Antineoplastic, Cell Division, Cell Line, Deoxycytidine, Dose-Response Relationship, Drug, Drug Synergism, Female, Humans, Immunohistochemistry, Indoles, Male, Mice, Nude, Neovascularization, Pathologic, Pancreatic Neoplasms, Placenta, Pregnancy, Pyrroles, Time Factors, Apoptosis, Angiogenesis Inhibitors, Xenograft Model Antitumor Assays, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Line, Tumor, Tissue Culture Techniques, Protein Kinase Inhibitors, Mice

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