gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Endostatin - albumin fusion protein improves in vitro and in vivo effectiveness in tumor therapy

Meeting Abstract

  • corresponding author presenting/speaker Ilhan Celik - Institut für Theoretische Chirurgie, Philipps- Universität Marburg, Deutschland
  • Carsten Dietz - Klinik für Visceral-, Thorax, und Gefäßchirurgie, Philipps- Universität Marburg
  • Oguzkan Sürücü - Institut für Theoretische Chirurgie, Philipps- Universität Marburg
  • Peter Mertins - ZLB Behring GmbH, P.O.Box 1230, 35002 Marburg
  • Oliver Kisker - Klinik für Visceral-, Thorax, und Gefäßchirurgie, Philipps- Universität Marburg

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO456

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Veröffentlicht: 20. März 2006

© 2006 Celik et al.
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Introduction: Endostatin is a potent endogenous inhibitor of angiogenesis. In several preclinical and clinical trials the in vitro and in vivo effectiveness could be demonstrated without side effects. Additionally it could be shown that continuous application with i.p. implanted pumps in mice is superior to bolus injections of endostatin and ensures effective plasma levels over a longer duration. Aim of the study was to investigate the antiangiogenic and anti-tumor effects in vitro and in vivo of a new albumin endostatin fusion protein (AFP-endostatin) with increased half-life.

Methods: Step 1: Generation/expression of recombinant human AFP-endostatin in yeast. Step 2: Pharmacokinetic studies of AFP-endostatin versus rh-endostatin (Calbiochem) applicated intravenously (i.v.) and subcutaneously (s.c.) to survey Cmax, half-life and optimal dosage. Measurement of endostatin serum levels by ELISA (Cytimmune). HUVEC migration assays with AFP- endostatin and rh-endostatin (Calbiochem) 0.03 – 40 µg/ml. Step 3: In male immuno-deficient mice ( SCID, 6-8 weeks old) BxPC-3 pancreatic cancer cells (2.5 x 106 in 0.2 ml RPMI 1640 medium) were implanted s.c. in the dorsa of the mice (n=7/group). Tumor volume was measured every 3-5 days with the digital calliper. Mice were randomised in therapy and control groups when tumor size reached 100 +/- 20 mm3. Animals in the 4 therapy groups were treated by s.c. AFP-endostatin application: 0.5 mg/kg/24h; 0.4 mg/kg/72h; 1.2 mg/kg/72h; 3.6 mg/kg/72h versus daily PBS application (n = 7/Gruppe) for 23 days. Tumor volume was measured every 3-5 days with the digital calliper.

Results: 1) Successful generation/expression of AFP–endostatin in yeast. 2) Significant increase of half-life for AFP- endostatin (56h) versus rh-endostatin (4.5h). Migration assay showed 66% inhibition (0.2 µg/ml) for AFP-endostatin versus 87% inhibition (rh-endostatin). 3) Similar tumor inhibition rate could be shown for 0.5 mg/kg/24h and 1.2 mg/kg/72h and a clear dose-response for 72 h application schedule (Table 1 [Tab. 1]). No side effects or weight loss was observed.

Conclusion: AFP–endostatin shows comparable in vitro effectivity to rh-endostatin. Effectiveness in tumor therapy is significantly higher compared to published rh-endostatin results (100 mg/kg/24h rh-endostatin versus 1.2 mg/kg/72h AFP- endostatin for an inhibition rate of 80%). Application frequency could be reduced with AFP-endostatin (every 3 days vs daily application), which leads to better patients compliance and reduced therapy costs.