Artikel
Differential growth inhibition of cerebral metastases by anti-angiogenic compounds depends on type of application and of vascular growth pattern
Die Effektivität der Inhibierung experimenteller zerebraler Metastasen durch anti-angiogene Substanzen wird durch den initialen Vaskularisationsphänotyp bestimmt.
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Autoren
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K.D. Martin
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Deutschland
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C. Schulze
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Deutschland
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P. Weigel
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Deutschland
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G. Schackert
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Deutschland
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M. Kirsch
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Deutschland
| Veröffentlicht: | 30. Mai 2008 |
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Gliederung
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Objective: Experimental melanoma metastases are susceptible to antiangiogenic treatment using endogenous inhibitors of angiogenesis such as endostatin. The purpose of this study was to evaluate synthetic angiogenesis inhibitors in murine models of brain metastases.
Methods: Two different murine melanoma metastases models were employed: first, a solitary tumor was induced by injection of 50,000 murine K1735 or human A375 melanoma cells into the right frontal lobe; secondly, hematogenous metastases into one hemisphere were induced by injection of 100,000 cells into the right internal carotid artery of nude mice. 20 mice served as controls for each tumor model. 8 mice / group were treated systemically with either a thalidomide analogue, a VEGFR2 blocker, or an integrin alpha5-beta3/5 antagonist.
Results: Whereas tumors induced by direct intracerebral deposition of tumor cells showed a largely classical vascularisation phenotype of sprouting angiogenesis, the hematogenous metastases relied initially on a cooption-like vascularisation phenotype. Solid melanoma metastases induced by direct intracerebral injection were more susceptible to daily low dose treatment using angiogenic compounds than multiple hematogenous metastases. Solitary metastases responded to the integrin antagonist with a 30% tumor reduction compared to negligible inhibition of hematogenously induced melanoma metastases. However, after 21 days, a marked reduction of vascularity was seen in both tumor types.
Conclusions: The efficacy of tumor growth inhibition by various anti-angiogenic substances depends on the mode of application and, therefore, the initial vascularisation type, namely cooptional vascularisation vs. sprouting angiogenesis. In traditional murine models of brain metastases, a significant tumor suppression was observed, whereas hematogenous metastases seem to prefer an initial cooptional angiogenesis before sprouting angiogenesis ensues. At this point, systemic antiangiogenic treatment was ineffective in preventing further tumor growth.
