Abstract
The cytoreductive effects of anti-transferrin receptor (anti-TfnR) immunotoxins (ITs) and of ricin toxin against tumour micromasses have been evaluated in a multicellular tumour spheroid (MTS) model. More than 600 (656) MTSs obtained with human breast carcinoma (MCF7) or rat glioblastoma (9L) cell lines were treated individually with ITs or toxin and the effects induced by the treatment were measured for each MTS as volume variation vs time by applying the Gompertz growth model. Two dose-dependent patterns of MTS growth were observed in MTSs of both cell lines in response to IT or toxin treatment: (1) complete inhibition of MTS growth ('sterilisation'); and (2) partial/complete inhibition ('heterogeneous response'). Within the range of IT or toxin concentrations resulting in partial inhibition of MTS growth, the sensitivity of treated MTSs was extremely heterogeneous (the cytoreductive effects varying between 0.1 and 4 logs of cells killed for a given IT or toxin concentration). Analysis of the post-treatment regrowth kinetics indicated that treated non-sterilised and control MTSs reached the same final limiting volumes. However, the doubling time estimated for the surviving cells of treated MCF7 and 9L MTSs ranged between 15 and 50 h, indicating that each MTS had individual growing potential. In conclusion, our results indicate that at substerilising IT concentrations individual heterogenicity of MTSs may greatly influence the cytoreductive potential of ITs. An implication of our study is that the efficacy of an IT treatment in eradicating disseminated micrometastases may not be predictable a priori. The MTS model that we describe in this paper may help in dissecting out factors limiting the effect of ITs in three-dimensional tumours.
Highlights
Because of their high cell selectivity and potent cell killing efficacv immunotoxins (ITs) could be ven useful in eradicating microaggregates of tumour cells escaping conventional therapies and as an adjuvant treatment for the prevention of tumour relapse (Vitetta et al.. 1993)
Heterogeneity of tumours at three-dimensional as well as at a single-cell level represents a serious limitation to the successful application of antineoplastic agents (Norton. 1985: Sutherland. 1988: Chignola et al.. 1994a)
a correct evaluation of the real effectiveness of IT-based therapeutic regimens should take into account the three-dimensional organisation of tumours as an element adding to the tumour heterogeneity observed at single-cell level
Summary
To make clear the principles of our data collection process and to simplify the description of assays involving a great number of experimental observations, we will first give a. D_W- OiStYrot ITS response to inmi in ins qualitative account of our results followed by a more represents a measure of the log kill in a single MTS treated rigorous quantitative analysis. Qualitative analysis The growth kinetics of treated and con- treatment the cytoreductive effects were highly trol mock-treated MTS was evaluated. Representative experiment: data are expressed as volume inc- The variable response of individual MTSs to treatment was rease of individual MTSs vs time. Whereas treated MTSs displayed heterogeneous growth behaviours depending on the IT concentrations used. At the higher concentrations the growth of MTS was completely inhibited at least within the time frame of our assays (see Figure 2bW 'sterilising concentrations') For each treatment. two patterns of altered growth kinetics I were observed at different doses of IT or toxin: 1. At the higher concentrations the growth of MTS was completely inhibited at least within the time frame of our assays (see Figure 2bW 'sterilising concentrations')
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