Effects of interferon-gamma and its interaction with retinoic acid on human neuroblastoma differentiation

Differentiation-promoting effects of interferon-gamma (IFN-gamma), both alone and in combination with retinoic acid (RA), were studied on the human neuroblastoma cell line, LA-N-5. The results show that IFN-gamma inhibited the growth and induced morphological differentiation in a dose- and time-dependent manner with measurable effects appearing at 20-40 IU/ml after 3 to 4 days of treatment in vitro. Acetylcholinesterase activity, used as a biochemical index of neuroblastoma differentiation, increased up to 2.5-fold in the presence of IFN-gamma with a half maximal concentration of approximately 100 IU/ml. Concomitantly, modest IFN-induced increases (less than or equal to 2-fold) in choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) activities were seen. Combination treatment of cells with IFN-gamma and RA resulted in synergistic effects on morphological differentiation, growth inhibition and induction of ChAT. Reversal of IFN-gamma's ability to influence neuroblastoma cell growth as well as potentiate the anti-tumor effects of RA was obtained in the presence of an antibody against the IFN-gamma receptor, implying receptor-mediated physiological events. Taken together, these data confirm the differentiating effects of IFN-gamma on human neuroblastoma cells and suggest that combination therapy with RA may be beneficial in the treatment of this disease.