No abstract

The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) receptor c-Met plays a crucial role in the development of the invasive phenotype of tumors and thus represents an attractive candidate for targeted therapies in a variety of malignancies, including human malignant melanoma (MM). In contrast to what has been shown previously, we were not able to detect any genetic alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the studied MM cell lines. Nevertheless, c-Met was constitutively active in these cell lines without exogenous HGF/SF stimulation. The active receptor was localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor SU11274 specifically decreased the phosphotyrosine signal at the focal adhesions sites, which was accompanied by a decrease in cell proliferation as well as an increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 significantly reduced the in vitro migratory capacity of MM cells in the modified Boyden-chamber assay. Administration of SU11274 significantly decreased primary tumor growth as well as the capacity for liver colony formation of MM cells in SCID mice. Our study provides the first evidence for an in vivo antitumor activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a valid target for the therapy of MM. Consequently, SU11274 treatment might represent a useful strategy for controlling melanoma progression and metastasis in patients with MM.

The evaluation of the radial electron density profile of a drug containing a sterically stabilized liposomal system is described. Using synchrotron small-angle X-ray scattering, we were able to characterize the hydrophilic shell of the polyethylene glycol chains. Using a Gaussian model for describing the electron density profile along the normal of the bilayer, we got an asymmetric distribution of PEGylated lipids in accordance with theoretical considerations. Moreover, we used anomalous X-ray scattering to study the localization of a hydrophobic drug (a kinase inhibitor), which revealed that these molecules are mainly located in the hydrocarbon chain region of the phospholipid bilayer.