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The Combination of -Interferon and Tumor Necrosis Factor Causes a Rapid and Extensive Differentiation of Human Neuroblastoma Cells¹

Pediatric Oncology Research Laboratory, G. Gaslini Children's Hospital, Largo Gerolamo Gaslini 5, 16148 Genoa, Italy

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 -interferon (IFN-) 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- plus TNF causes extensive and generalized differentiation of NB cells toward a neuronal phenotype. Both IFN- 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- 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-/TNF results in the induction of a differentiated phenotype, as indicated by the increased expression of the M_r 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- and TNF should be considered for experimental clinical trials in neuroblastoma.

¹ 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.

² To whom requests for reprints should be addressed.

Received 7/22/91. Accepted 12/ 3/91.

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