HETEROGENEOUS RESPONSE OF INDIVIDUAL MULTICELLULAR TUMOR SPHEROIDS TOIMMUNOTOXINS AND RICIN TOXIN

The cytoreductive effects of anti-transferrin receptor (anti-TfnR) imm unotoxins (ITs) and of ricin toxin against tumour micromasses have bee n evaluated in a multicellular tumour spheroid (MTS) model. More than 600 (656) MTSs obtained with human breast carcinoma (MCF7) or rat glio blastoma (9L) cell lines were treated individually with ITs or toxin a nd the effects induced by the treatment were measured for each MTS as volume variation vs time by applying the Gompertz growth model. Two do se-dependent patterns of MTS growth were observed in MTSs of both cell lines in response to IT or toxin treatment: (1) complete inhibition o f MTS growth ('sterilisation'); and (2) partial/complete inhibition (' heterogeneous response'). Within the range of IT or toxin concentratio ns resulting in partial inhibition of MTS growth, the sensitivity of t reated MTSs was extremely heterogeneous (the cytoreductive effects var ying between 0.1 and 4 logs of cells killed for a given IT or toxin co ncentration). Analysis of the post-treatment regrowth kinetics indicat ed that treated non-sterilised and control MTSs reached the same final limiting volumes. However, the doubling time estimated for the surviv ing cells of treated MCF7 and 9L MTSs ranged between 15 and 50 h, indi cating that each MTS had individual growing potential. In conclusion, our results indicate that at substerilising IT concentrations individu al heterogeneity of MTSs may greatly influence the cytoreductive poten tial of ITs. An implication of our study is that the efficacy of an IT treatment in eradicating disseminated micrometastases may not be pred ictable a priori. The MTS model that we describe in this paper may hel p in dissecting out factors limiting the effect of ITs in three-dimens ional tumours.