Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo

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Author list: Sckell A
Publisher: BMC (part of Springer Nature)
Publication year: 2007
Volume number: 7
Issue number: 49
Number of pages: 8
ISSN: 1471-2407
Languages: English-Great Britain (EN-GB)


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. © 2007 Klenke et al; licensee BioMed Central Ltd.


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Last updated on 2019-13-08 at 00:15