MULTICELLULAR RESISTANCE - ANOTHER MECHANISM FOR MULTIDRUG-RESISTANCE

Cells cultured as spheroids present an heterogeneity similar to that o f tumours in vivo. In the spheroid peripheral lavers, cells are prolif erating deeper cells are non-cycling, when in the aggregate centre, ce lls form often a necrotic core. A multicellular resistance appears in spheroids, it is a result of the cell contact to other cells (homogene ous or heterogeneous cells) and/or to the extracellular matrix, The me chanism of this resistance is not known, nevertheless, it can be hypot hesised to be linked to the spheroid centre hypoxia; to the quiescence of a largely action of the cell population and to the apoptose inhibi tion due to the cell contact. The '' classical '' or '' unicellular '' mechanisms of resistance, as mdr1, MRP, can coexist with the multicel lular resistance; but are nor responsible for this resistance The sphe roid model of culture is a good opportunity to study a resistance type which looks close to the tumour resistance found in vivo in mice and in patients A new class of therapeutic molecules appears that can reve rse this multicellular resistance, inhibit tumours growth and preclude metastases The principal mechanism of action of this new pharmacologi cal class appears to be the disruption of the intercellular adhesion f orces. Preliminary results obtained with these compounds in patients a re promising.