GROWTH-INHIBITION BY INTERFERON-BETA AND INTERFERON-GAMMA OF MDA-886LN MONOLAYER CELLS AND MULTICELLULAR TUMOR SPHEROIDS - A DIFFERENTIATION THERAPY MODEL FOR SQUAMOUS-CELL CARCINOMA

Objective: The ability of interferon beta (IFN-beta) and interferon ga mma (IFN-gamma) to modulate growth and differentiation of squamous car cinoma was studied. Design: Two squamous carcinoma models (MDA. 886Ln monolayer cells and multicellular tumor spheroids [MTSs], an in vivo s ystem with three-dimensional in vivo-like structure) were used. Effect s of interferons were examined with growth and differentiation assays. Results: In 5-day monolayer growth assays, both interferons (IFNs) ex hibited dose-dependent growth inhibition between 0 and 10(4) U/mL; IFN -gamma was more inhibitory than IFN-beta (inhibitory concentration for 50% inhibition of 9 and 900 U/mL for IFN-gamma and IFN-beta, respecti vely). Multicellular tumor spheroid growth was examined by sizing MTSs over a 9-day growth period. Multicellular tumor spheroids were resist ant to IFN-beta with exposures of up to 50 000 U/mL. Similarly, MTSs w ere resistant to IFN-gamma for the first several days, with growth inh ibition becoming evident between days 7 to 9 of culture. As a marker o f differentiation, transglutaminase activity was quantified after 5 da ys of treatment. Both IFNs induced increased transglutaminase activity in monolayer cells: IFN-beta was twice as effective as IFN-gamma. In contrast, 5-day treated MTSs showed no induction although their endoge nous activity was higher. Flow cytometric analysis of monolayer cells for induction of class I and II major histocompatibility complex showe d that both IFNs induced class I antigens but only IFN-gamma could ind uce class II. Conclusions: With their three-dimensional architecture, MTSs were more resistant to IFN-induced growth inhibition and differen tiation induction than monolayer cells. Thus, mode of growth (monolaye r vs MTS) is an important factor in responsiveness to IFN treatment; t his suggests that MTSs may produce information that is more relevant t o in vivo usage than monolayer cells.