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Morphological Differentiation of Human Neuroblastoma Cell Lines by a New Synthetic Polyprenoic Acid (E5166)¹

Children's Research Hospital [T. Su.] and Department of Pediatrics [T. Sa., T. M., Y. H., T. H.], Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602, Japan; Eisai Co., Ltd. [Y. S., M. O., O. T.], Bunkyo, Tokyo 112, Japan; and Institute of Child Health [J. T. K.], London WC1 1EH, England

The prognosis of patients with advanced neuroblastoma remains poor despite recent progress in chemo/radiotherapy. Therapeutic trials on the induction of differentiation of neuroblastoma by chemical and biological agents have been attempted to improve patients' prognosis. Recently a new synthetic polyprenoic acid, E5166, having retinoic acid properties, has been described. In this study two human neuroblastoma cell lines, KP-N-RT(LN) and SK-N-DZ, were treated in vitro by E5166. Morphological differentiation of KP-N-RT(LN) and SK-N-DZ cells could be induced by E5166 in the presence of 1.7 x 10^-5 M E5166 for 10 days in culture. Levels of catecholamines (dopamine, adrenaline, and noradrenaline) were not elevated in the E5166-differentiated cells. E5166-induced differentiation may not be cyclic AMP dependent, since levels of cyclic AMP did not increase after exposure of cells to this agent. No significant increase in neuron-specific enolase levels could be demonstrated in E5166-treated neuroblastoma as compared to control untreated cells. E5166 treatment of KP-N-RT(LN) and SK-N-DZ cells was found to inhibit colony formation in soft agar in a dose-dependent manner. Colonies of KP-N-RT(LN) cells in the presence of E5166 showed morphological differentiation as defined by the expression of long neurite processes.

E5166 is a less toxic reagent than the retinoic acids used for the induction of differentiation, it can be administered to patients p.o., and the concentration of E5166 which induces the morphological differentiation in vitro can be achievable in vivo. Therefore our study suggests that E5166 could be a useful therapeutic agent in advanced neuroblastoma to differentiate residual anaplastic tumor cells to a benign form (ganglioneuroma) after surgery and chemotherapy.

¹ This work was supported in part by grants for cancer research from the Ministry of Health and Welfare and from the Ministry of Education (No. 59480236) of Japan and by a 1986 Research Grant for the Promotion of Immunology Research from the Dr. Shimizu Foundation.

² To whom requests for reprints should be addressed.

Received 8/ 4/86. Revised 4/13/87. Revised 7/ 9/87. Accepted 7/13/87.

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