In vitro studies have demonstrated that retinoic acid (RA) can alter the growth and morphologic characteristics of human neuroblastoma cells in a manner that is consistent with a reduced expression of the malignant phenotype. These effects may reflect the ability of this retinoid to promote celullar differentiation, thus causing neuroblastoma cells to acquire more neuron-like properties. One aim of this project is to test this possibility. A number of well-characterized biochemical parameters will be investigated in association with RA treatment of human neuroblastoma cell lines. These experiments will further assess the ability of RA to induce physiologic-like qualities of maturation in neuroblastoma cells and will provide a means of establishing sensitive quantitative assays for assessing cellular maturation in our mechanistic studies. Results obtained by the in vitro assay systems will be further tested in an in vivo nude-mouse model to confirm and correlate RA-induced reduction in tumorigenicity and maturational processes. This in vivo model may also serve to emphasize the clinical potentials and limitations of RA treatment for control of neuroblastoma in humans. We will also attempt to define neuroblastoma phenotypes that vary in their sensitivity to RA treatment. As such, the responses of cells to RA will be compared wih their reactivity to a variety of monoclonal antibodies. Monoclonal antibody reactivity with the neuroblastoma cells will also be evaluated during RA treatment in an effort to define a general "profile" of RA-induced antigenic changes that occur. In a clinical setting, such use of monoclonal antibodies would allow for the identification of neuroblastoma phenotypes that vary in RA treatment responses and prognosis, and provide a convenient means of following in vivo tumor-cell maturational processes. Finally, we will initiate mechanistic studies for assessing the molecular action of RA on neuroblastoma cell differentiation based upon the following areas of investigation: 1) the interrelationship between RA and the cyclic AMP system; 2) RA regulation of a putative neuroblastoma oncogene (N-myc); and 3) RA-induced changes of a cellular tumor antigen (termed p53) that has been implicated in the control of cell division and differentiation processes. Results of these studies should provide a basis for future in-depth investigations into deliniating the molecular mechanisms of RA on tumor cell differentiation using human neuroblastoma as a model system.