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Organische Chemie I - Prof. Dr. Rainer Schobert

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Antimetastatic Agents

Conventional cancer therapy is mainly concerned with the management of the primary tumour despite the fact that over 90% of all cancer deaths are due to metastases.
The "metastatic cascade" is a multi−step process commencing by an alteration of cell−cell adhesion within the primary tumour and of the cell interaction with the surrounding extracellular matrix (ECM), followed by an invasion of cancer cells into stromal cell layers, their intravasation into the lumina of blood vessels, transport by the blood stream, extravasation at distinct organ sites and penetration of the parenchyma there, and eventually their adaptation of the newly colonised microenvironment. Once the micrometastases have grown larger than 2−3 mm they need to induce the sprouting of new blood vessels from neighbouring vasculature by secreting vascular endothelial growth factors (VEGF) or by releasing them from the ECM. The resulting new tumour blood vessels are physiologically different from regular ones, which allows to selectively damage them with vascular−disrupting agents (VDA). We develop drugs that interfere with indidual steps of this "metastatic cascade". E.g.: A copper genistein complex (1) was found to reduce the levels of ECM−degrading metalloproteinases MMP−2 and MMP−9 in cancer cells.
It also enhances the cell−cell contacts by recruiting β−catenin to the cell perimeter. β−Catenin is a mediator of cell adhesion, yet also a transcriptional coactivator of prometastatic genes once translocated to the nucleus.
We developed imidazole derivatives of the natural VDA combretastatin A4 that combine the VDA effect with an improved cytotoxicity, with antiinvasive effects, and a good tolerance by animals, e.g. brimamin shown right. (2;3)

1 J Inorg Biochem, 127, 2013, 107
2 J Med Chem, 53, 2010, 6595
3 Invest New Drugs, 33, 2015, 541

Verantwortlich für die Redaktion: André Wetzel

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