[Anti-metastatic effects of serine protease inhibitors: animal models for analysis].
To date, no effective adjuvant drug preventing the aggressive spread of tumour cells in late stages of cancer disease or at the time-point of primary tumour removal is available. Although proteases, including members of the large serine protease family, were shown to be promising targets for an anti-metastatic cancer therapy, synthetic protease inhibitors (SPIs) have so far failed to be introduced into the clinic. In addition to considerations in the design of classical in vivo -tests of SPIs as cancer therapy agents, we here review our findings with a straightforward, highly sensitive and very fast in vivo metastasis model and its implications in the development of efficient anti-metastatic SPIs. The lacZ-tagging of tumour cells of this very aggressive T-cell lymphoma model allowed highly sensitive and reproducible detection of metastases within seven days after tumour cell inoculation by X-gal staining of whole organs, allowing cost-effective and material-saving side-by-side screening of a series of SPIs with different specificities for different serine proteases. By establishment of specificity/antimetastatic efficacy correlations we identified coagulation factor Xa as one important target of anti-metastatic SPIs and could use this information for the subsequent design and optimization of factor Xa-specific lead structures.


CONCLUSIONS
We exemplify the usefulness of high-throughput in vivo analysis to direct optimization of lead structures and how this may allow unexpected insight into the molecular biology of metastasis.
Krüger
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Institut für Experimentelle Onkologie und Therapieforschung, Klinikum rechts der Isar der Technischen Universität, Ismaningerstrasse 22, 81675 München. achim.krueger@lrz.tu-muenchen.de
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D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*
D015842:Serine Proteinase Inhibitors