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.
Wuarin
L
L
Department of Pathology, UCLA School of Medicine 90024.
Verity
M A
MA
Sidell
N
N
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D009447:Neuroblastoma; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D014212:Tretinoin / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D015124:8-Bromo Cyclic Adenosine Monophosphate; D014212:Tretinoin; D007371:Interferon-gamma; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase