of the Max - MDC

Development of an inhibitor of metastasis
Metastasis remains the most serious cause for the high mortality
of cancer patients. Therefore, the search for new targets
and the development of inhibitors of tumor cell resettlement
and metastatic growth has been an ongoing challenge.
One decisive step of the metastatic cascade is the formation
of tumor cell aggregates within the blood circulation and
the subsequent interaction with the endothelium.
Previous observations demonstrated that specific liposomes
not only facilitated the formation of complexes consisting
of activated platelets and breast cancer cells in vitro, but
were also found inside of these complexes. This finding
induced the idea to exploit the accumulation of vesicles
inside of micro thrombi for targeting purposes using a liposomal
formulation containing a cytotoxic substance together
with a haemostatic inhibitor. We expected this dual
approach to disturb the interaction of circulating tumor
cells with platelets and/or with the endothelial membrane
by restricting simultaneously platelet and tumor cell functionality.
For this purpose small unilamellar liposomes were designed
to encapsulate Perifosine (OPP) and Dipyridamole (DIP).
These vesicles were characterized for their physico-chemical
properties and for stability. Under in vitro conditions, complex
formation between platelets and human MT-3 breast
cancer cells, and adhesion of platelets to immobilized MT-3
cells could be significantly inhibited with the DIP/OPP- liposomes.
In addition, using MT3 breast carcinoma cells in an
experimental metastasis model in nude mice, the liposomes
also reduced the formation of lung metastases. Ongoing
investigations focus on the molecular processes involved in
the interplay between platelets and tumor cells and on the
influence specific lipids exert in this context.
In a second study, the influence of membrane organization
on the interaction between tumor cells and endothelial cells
during adhesion was studied. The results indicate a specific
impact of domain organization and fluidity of the cell membrane
on tumor cell binding. A highly fluid plasma mem-
Figure 1. Expression of epidermal growth
factor receptor in the non-small cell lung
cancer Lu7466; comparison of patient
tissue with xenograft (P4) and with the
A431 epidermoid carcinoma.
144 Cancer Research