Research article

Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo

Frank M Klenke¹ , Amir Abdollahi² , Elisabeth Bertl³ , Martha-Maria Gebhard⁴ , Volker Ewerbeck⁵ , Peter E Huber² and Axel Sckell⁶

¹Department of Orthopedic Surgery, Inselspital, University of Bern, CH-3010 Bern, Switzerland

²Department of Radiation Oncology, German Cancer Research Center, INF 280, D69120 Heidelberg, Germany

³Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, INF 280, D-69120 Heidelberg, Germany

⁴Department of Experimental Surgery, University of Heidelberg, INF 365, D-69120 Heidelberg, Germany

⁵Department of Orthopedic Surgery, University of Heidelberg, Schlierbacher Landstrasse 120a, D-69118 Heidelberg, Germany

⁶Department of Trauma and Reconstructive Surgery, Charité University Medical Center, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany

author email corresponding author email

BMC Cancer 2007, 7:49doi:10.1186/1471-2407-7-49

Published:	17 March 2007

Abstract

Background

As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore, additional therapies such as antiangiogenesis represent a promising strategy for overcoming limitations in chondrosarcoma therapy. There is strong experimental evidence that SU6668, an inhibitor of the angiogenic tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1 can induce growth inhibition of various primary tumors. However, the effectiveness of SU6668 on malignant primary bone tumors such as chondrosarcomas has been rarely investigated. Therefore, the aim of this study was to investigate the effects of SU6668 on chondrosarcoma growth, angiogenesis and microcirculation in vivo.

Methods

In 10 male severe combined immunodeficient (SCID) mice, pieces of SW1353 chondrosarcomas were implanted into a cranial window preparation where the calvaria serves as the site for the orthotopic implantation of bone tumors. From day 7 after tumor implantation, five animals were treated with SU6668 (250 mg/kg body weight, s.c.) at intervals of 48 hours (SU6668), and five animals with the equivalent amount of the CMC-based vehicle (Control). Angiogenesis, microcirculation, and growth of SW 1353 tumors were analyzed by means of intravital microscopy.

Results

SU6668 induced a growth arrest of chondrosarcomas within 7 days after the initiation of the treatment. Compared to Controls, SU6668 decreased functional vessel density and tumor size, respectively, by 37% and 53% on day 28 after tumor implantation. The time course of the experiments demonstrated that the impact on angiogenesis preceded the anti-tumor effect. Histological and immunohistochemical results confirmed the intravital microscopy findings.

Conclusion

SU6668 is a potent inhibitor of chondrosarcoma tumor growth in vivo. This effect appears to be induced by the antiangiogenic effects of SU6668, which are mediated by the inhibition of the key angiogenic receptor tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1. The experimental data obtained provide rationale to further develop the strategy of the use of the angiogenesis inhibitor SU6668 in the treatment of chondrosarcomas in addition to established therapies such as surgery.