Ethylnitrosourea (ENU) is a potent chemical carcinogen which selectively induces tumors of the nervous system when administerd transplacentally into animals. The neural tumors produced have striking histological, histochemical and biochemical similarities to the tumors encountered in human pathology. Glycosphingolipids have been implicated as being important in cell surface recognition structures and may involve in a variety of cell surface phenomena. The present proposal is to investigate sequentially the preneoplastic and neoplastic changes that occur in the composition and metabolism of glycosphingolipids of the transformed cells. The transformed cells are consistently produced in the trigeminal nerve of rats soon after exposure to a single dose of ENU. The changes in the membrane composition and metabolism will be correlated with changes in the cellular morphology and differentiation occurring during the tumor growth. It is suggested that the alkylchains of ceramide moiety in the membranes may determine the activity of glycsyltransferases. We have observed remarkable differences in the alkylchains of GM3, the key intermediate in the metabolism of gangliosides, during normal differentiation and also during oncogneic cell-transformation. It is planned to study the importance of alkylchains in the regulation of subsequent attachment of carbohydrate moieties for the synthesis of higher gangliosides. The effect of retinoids on the induction and growth of neural tumors produced by ENU will be studied. It is planned to determine if the expected inhibitory or retarding effect of retinoids on tumors is mediated via the cell-surface glycosphingolipids. The results should help to understand the role of glycosphingolipids in the growth and control of transformed, neoplastic and malignant cells.
