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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA016853-08
Application #
3164530
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1974-09-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1987-06-30
Support Year
8
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Eunice Kennedy Shriver Center Mtl Retardatn
Department
Type
DUNS #
City
Waltham
State
MA
Country
United States
Zip Code
McCluer, R H; Ullman, M D; Jungalwala, F B (1989) High-performance liquid chromatography of membrane lipids: glycosphingolipids and phospholipids. Methods Enzymol 172:538-75
Kunemund, V; Jungalwala, F B; Fischer, G et al. (1988) The L2/HNK-1 carbohydrate of neural cell adhesion molecules is involved in cell interactions. J Cell Biol 106:213-23
Chou, D K; Schwarting, G A; Evans, J E et al. (1987) Sulfoglucuronyl-neolacto series of glycolipids in peripheral nerves reacting with HNK-1 antibody. J Neurochem 49:865-73
McCluer, R H; Ullman, M D; Jungalwala, F B (1986) HPLC of glycosphingolipids and phospholipids. Adv Chromatogr 25:309-53
Chou, D K; Ilyas, A A; Evans, J E et al. (1986) Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy. J Biol Chem 261:11717-25
Koul, O; Jungalwala, F B (1986) UDP-galactose: ceramide galactosyltransferase of rat central nervous system myelin during development. Neurochem Res 11:231-9
Chou, K H; Nolan, C E; Jungalwala, F B (1985) Subcellular fractionation of rat sciatic nerve and specific localization of ganglioside LM1 in rat nerve myelin. J Neurochem 44:1898-912
Jungalwala, F B; Koul, O; Stoolmiller, A et al. (1985) Regulation of cerebroside and sulfatide metabolism in glia cells. J Neurochem 45:191-8
Chou, K H; Ilyas, A A; Evans, J E et al. (1985) Structure of a glycolipid reacting with monoclonal IgM in neuropathy and with HNK-1. Biochem Biophys Res Commun 128:383-8
Figlewicz, D A; Nolan, C E; Singh, I N et al. (1985) Pre-packed reverse phase columns for isolation of complex lipids synthesized from radioactive precursors. J Lipid Res 26:140-4