Embryonal and primitive neuroepithelial tumors constitute a significant number of the pediatric CNS neoplasms. Their poorly understood, complex biologic activity makes their diagnostic classification difficult and their therapeutic response unpredictable. Fetal neural cells may be a selective target for neoplastic development and the embryonal tumors demonstrate a potential to differentiate along the sequential stages of normal neurocytogenesis. Tumor arrest or regression has been associated with increased cellular maturation, and substances known to promote differentiation have been proposed as a therapeutic approach. The endogenous substances that may play a role in modulating divergent differentiation in human embryonal CNS tumors have not been characterized. Evidence from developing vertebrates and invertebrates suggest that biogenic monoamines and in particular, the indoleamines may act as early neuroregulators and their role in neoplastic differentiation in CNS tumors has yet to be studied. This research will examine the developmental biologic activity of the indoleamines serotonin and tryptamine and the serotonin-associated neuropeptides in embryonal CNS tumors using the neuroepithelial component of the OTT-6050 mouse teratoma, a well-characterized and highly promising experimental model for neoplastic neural differentiation. Correlative studies with available human tumors will also be performed. Studies will focus on defining two aspects of the amines in these tumors. First, neoplastic serotonin and tryptamine membrane receptor ontogeny as defined by specific ligand binding and second, functional development will be examined to analyze these amines as regulators of early divergent differentiation in embryonal neural tumors. Ontogenetic analyses will include examination of specific agonist and antagonist binding sites by autoradiography. Functional studies will examine the indoleamine effects on cytodifferentiation, growth kinetics, and in vivo tumorigenicity. The ontogeny of the indoleamine receptors will be correlated to the development of endogenous indoleamine metabolic systems as detected by HPLC and histofluorescent techniques. Understanding the role of indoleamines in the regulation of neoplastic neural maturation and growth may lead to a better insight into these processes, permitting better discrimination of, and more precise therapies to, embryonal human CNS tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022455-03
Application #
3404868
Study Section
Pathology A Study Section (PTHA)
Project Start
1986-04-15
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1990-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Britt, S G; Chiu, V W; Redpath, G T et al. (1992) Elimination of ascorbic acid-induced membrane lipid peroxidation and serotonin receptor loss by Trolox-C, a water soluble analogue of vitamin E. J Recept Res 12:181-200
Hubbard, C M; Redpath, G T; Macdonald, T L et al. (1989) Modulatory effects of aluminum, calcium, lithium, magnesium, and zinc ions on [3H]MK-801 binding in human cerebral cortex. Brain Res 486:170-4
VandenBerg, S R; Gonias, S L (1989) Covalent complexes of albumin with serotonin, ketanserin and lysergic acid antagonize the activity of serotonin in human platelets. Life Sci 44:1777-85
Caccamo, D V; Katsetos, C D; Frankfurter, A et al. (1989) An immunohistochemical characterization of the primitive and maturing neuroepithelial components in the OTT-6050 transplantable mouse teratoma. Neuropathol Appl Neurobiol 15:389-405
VandenBerg, S R; Britt, S G; Redpath, G T et al. (1989) 5-Hydroxytryptamine2 (5-HT2) structure-function relationships of the nitro and amino phenylpiperazines on intact human platelets. Biochem Pharmacol 38:4237-44
Hall, S W; VandenBerg, S R (1989) Solid phase extraction of the zwitterionic detergent chaps. Prep Biochem 19:1-11
Britt, S G; Gonias, S L; Sanders, J M et al. (1988) Agonist and antagonist activities of arylpiperazines at human platelet serotonin2 receptors. J Pharmacol Exp Ther 247:965-70
Vandenberg, S R; Herman, M M; Rubinstein, L J (1987) Embryonal central neuroepithelial tumors: current concepts and future challenges. Cancer Metastasis Rev 5:343-65