Neuroblastoma (NB), a tumor originating from the sympathetic nervous system, is the most common extracranial neurological tumor of childhood. Human NB cells may differentiate in vitro under treatment with biological agents, as γ-interferon (IFN-γ) and tumor necrosis factor (TNF). Unfortunately, NB cell lines resistant to the differentiation-inducing effects of both drugs have been observed. Here we demonstrate that a combination of IFN-γ plus TNF causes extensive and generalized differentiation of NB cells toward a neuronal phenotype. Both IFN-γ and TNF, given alone, moderately reduced cell growth and induced partial morphological maturation. Their combination further reduced cell proliferation. The combined treatment gave a synergistic rather than additive cytostatic effect, documented also by a dramatically enhanced differentiation toward a neuronal morphology. Membrane immunofluorescence showed a homologous and heterologous up-regulation of IFN-γ receptor, as well as a marked induction of HLA Class I antigens and, to a lesser extent, of Class II antigens on NB cells induced to differentiate. Treatment of NB cell lines with IFN-γ/TNF results in the induction of a differentiated phenotype, as indicated by the increased expression of the Mr 160,000 and 200,000 neurofilament proteins and that of microtubule-associated proteins. Evaluation of biochemical markers of neuronal differentiation confirmed the ability of the combined treatment to induce neuroblast maturation. These results suggest that the combination of IFN-γ and TNF should be considered for experimental clinical trials in neuroblastoma.

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Supported by the Italian Association for Cancer Research, Milan, Italy; by Ricerca Corrente Gaslini Grant 901702C; and by Ricerca Finalizzata Gaslini Grant RF23-B.1.

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