gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Efficacy of CXCR2 inhibition on tumor angiogenesis in pancreatic cancer

Meeting Abstract

  • corresponding author presenting/speaker Ulrike Albrecht - Chirurgische Klinik und Poliklinik-Großhadern, LMU München, Deutschland
  • Bettina Schwarz - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Sabine Schroeferl - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Gerald Schmid - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Christoph Baumann - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Ivan Ischenko - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Markus Guba - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Christopher Heeschen - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Karl-Walter Jauch - Chirurgische Klinik und Poliklinik-Großhadern, LMU München
  • Christiane J. Bruns - Chirurgische Klinik und Poliklinik-Großhadern, LMU München

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO457

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dkk2006/06dkk567.shtml

Veröffentlicht: 20. März 2006

© 2006 Albrecht et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Many tumor cells, including pancreatic cancer, are capable to produce pro-angiogenic factors and to induce neo-vascularization. The chemokine interleukin 8 (CXCL8) has a profound angiogenic potential on endothelial cells through interaction with the receptor CXCR2. The aim of the study was to evaluate the activity of CXCR2 inhibition in a human pancreatic cancer nude mouse model.

Using ELISA the interleukin 8 (IL-8) concentration in conditioned media of different pancreatic cell lines - L3.6pl, FG, AsPC, BxPC-3, MIA PaCa - and human umbilical vein endothelial cells (HUVECs) was analyzed after six days of cultivation. Furthermore, we examined the expression of CXCR2 on all cell lines by FACS. To demonstrate in vitro the anti-angiogenic effect of CXCR2 inhibition HUVECs were treated both in a WST cell proliferation assays as well as in a spheroid assay with SB 225002, an antagonist of IL-8 binding to CXCR2. Following orthotopic injection of human pancreatic tumor cells (L3.6pl), we treated the animals starting 8 days after tumor cell injection with SB 225002 (3,2mg/kg), Gemcitabine (50mg/kg), combination therapy or vehicle alone by intraperitoneral application. The animals were scarified after 21 days of therapy and tumor size as well as metastases were evaluated.

ELISA confirmed the expression of IL-8 in the supernatant of all cell lines, especially L3.6pl cells produced an increasing amount over six days. FACS analysis showed that all tested cell lines expressed the CXCR2 receptor except L3.6pl. With the WST proliferation assay we demonstrated reduced proliferation of HUVECs treated with SB 225002 (IC 50= 0,15 µM). The vascular sprouting of VEGF- stimulated (20ng/ml) HUVEC spheroids was significantly inhibited at a concentrations of 0,1 µM. In vivo the application of SB 225002 resulted in a significant growth inhibition of orthotopic pancreatic tumors with a tumor size of 38% compared to the size of control tumors at the end of the therapy, which was similar to the efficacy of combination therapy (33%). Monotherapy with Gemcitabine resulted in a tumor size of 45% of untreated control tumors.

Taken together, SB 225002 shows an anti-angiogenic acticity in vitro and leads a profound reduction of pancreatic tumor growth in vivo. However, combination therapy with Gemcitabine appear to have no additive or synergistic activity. These data suggest that the inhibition of the chemokine receptor CXCR2 appears to be an effective anti-angiogenic therapy approach against pancreatic cancer. Further research has to be performed to evaluate the efficacy of combining CXCR2 inhibitors with conventional chemotherapy.