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Enhancement by Retinoic Acid and Dibutyryl Cyclic Adenosine 3':5'-Monophosphate of the Differentiation and Gene Expression of Human Neuroblastoma Cells Induced by Interferon¹

Divisions of Infectious Diseases [T. H., G. E. H., B. R. G. W.], Hematology/Oncology [D. M.], and Pathology [H. Y.], Research Institute, The Hospital for Sick Children, and Departments of Molecular and Medical Genetics [G. E. H., B. R. G. W.] and Pathology [H. Y.], University of Toronto, Toronto, Ontario, Canada

Human neuroblastoma cell lines are induced to differentiate and display neuronal phenotypes when treated with interferon (IFN)-₂, retinoic acid (RA), or dibutyryl cyclic AMP (dbcAMP). We investigated the effects of combinations of these agents in induction-differentiation in the neuroblastoma cell line, NUB-6. The inductive effect of IFN-₂ was markedly enhanced when used in combination with RA or dbcAMP. In parallel, RA or dbcAMP also enhanced the level of 2'-5'-oligoadenylate (2–5A) synthetase, an enzyme induced by IFNs and implicated in their biological action. The levels of another IFN-inducible enzyme, p68 kinase, were not enhanced by the combination treatments. The enhancement effects appeared to be exerted largely at the posttranscriptional level as both RA and dbcAMP stabilized IFN-induced 2–5A synthetase mRNA, resulting in increased enzyme activity. Thus, the 2–5A synthetase system is likely involved in mediating the IFN-₂-induced differentiation of neuroblastoma cells and may also mediate the enhancement effects of RA and dbcAMP on IFN activity in these cells. These results also provide a rational basis for establishing a combination therapeutic approach for the treatment of neuroblastoma.

¹ This research was supported by grants from the National Cancer Institute of Canada to B. W. and H. Y.

² Present address: Division of Molecular Biology, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129.

³ To whom requests for reprints should be addressed, at Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.

Received 12/12/91. Accepted 5/23/91.

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