gms | German Medical Science

121. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

27. bis 30.04.2004, Berlin

Efficacy of src kinase inhibitors in combination with Gemcitabine on human pancreatic cancer growing orthotopically in nude mice

Vortrag

  • presenting/speaker Maksim Yezhelyev - Chirurgische Klinik und Poliklinik-Großhadern, LMU München, München, Deutschland
  • I. Ischenko - Chirurgische Klinik und Poliklinik-Großhadern, LMU München, München, Deutschland
  • M. Guba - Chirurgische Klinik und Poliklinik-Großhadern, LMU München, München, Deutschland
  • A. Ryan - AstraZeneca, Macclesfield, England
  • A. Barge - AstraZeneca, Macclesfield, England
  • K.W. Jauch - Chirurgische Klinik und Poliklinik-Großhadern, LMU München, München, Deutschland
  • C.J. Bruns - Chirurgische Klinik und Poliklinik-Großhadern, LMU München, München, Deutschland

Deutsche Gesellschaft für Chirurgie. 121. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 27.-30.04.2004. Düsseldorf, Köln: German Medical Science; 2004. Doc04dgch0671

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgch2004/04dgch233.shtml

Veröffentlicht: 7. Oktober 2004

© 2004 Yezhelyev 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

Introduction

Although src kinase overexperssion has been reported in human pancreatic cancer there exist no studies about the anti-tumor effect of src kinase inhibition in vivo as mono-therapy or in combination with chemotherapy. The purpose of this study was to evaluate the efficacy of a novel src kinase inhibitor (AZM 475271) in combination with chemotherapy (Gemcitabine) on human pancreatic cancer growing orthotopically in nude mice.

Materials and methods

Following injection of 1x106 L3.6pl human pancreatic cancer cells into the pancreas of nude mice, 7 days later groups of nude mice were treated with 25 and 50mg/kg of src tyrosine kinase inhibitor by oral feeding alone and in combination with intraperitoneal injection of Gemcitabine (50mg/kg 2x/week). All animals were sacrified on day 32. Primary pancreatic tumor samples were used for immunohistochemical analysis for proliferation (Ki67) and cell death (TUNEL). In vitro, FACS analysis was perfomed to quantify the amount of tumor cell death.

Results

The average pancreatic tumor weight was 90+49, 290+160, 500+50, 508+205, 510+117 and 1125+460 mg following therapy with 50 and 25mg/kg AZM in combination with Gemcitabine, 50, 25 mg/kg AZM alone, Gemcitabine alone and controls, respectively. No liver and lymph node metastases were detected following therapy with 50 mg/kg AZM alone or in combination with Gemcitabine. The cytotoxic effect of Gemcitabine on L3.6pl cells by inducing apoptosis was significantly potentiated in combination with AZM in vitro using fluorescence-activated cell sorting (FACS) that corresponded with the results of immunohistochemical TUNEL analyses of tumor sections in vivo. However, treatment with Gemcitabine in combination with AZM 50mg/kg still caused significantly higher amount of apoptotic cells than either treatment alone (54+18). Reduced numbers of proliferating cells were found in tumors treated with AZM 50 and 25 mg/kg alone or AZM 50mg/kg in combination with Gemcitabine (275+33, 178+26, 159+28, respectively) as compared to controls (480 + 14) by immunohistochemical analyses of tumor sections for proliferating cells (Ki-67).

Conclusion

In summary, our experiments indicate that therapeutic strategies to inhibit src kinase activity in combination with Gemcitabine reveal a significant anti-tumor effect on human L3.6pl pancreatic carcinoma growing in nude mice. This effect is mediated in part by enhancing the cytotoxic effects of Gemcitabine with induction of apoptosis in vivo and in vitro, in part by prevention of proliferation of tumor cells in vivo.