DETERMINANTS OF THE RESPONSE OF NEUROBLASTOMA-CELLS TO DNA-DAMAGE - THE ROLES OF PRETREATMENT CELL MORPHOLOGY AND CHEMICAL NATURE OF THE DAMAGE

Chemotherapeutic agent-induced DNA cleavage gives rise to apoptosis in a subpopulation of SK-N-SH human neuroblastoma cells; the remaining c ells undergo Schwann cell-like differentiation. Like other neural cres t and primitive neurectodermal tumor-derived cell lines, SK-N-SH cultu res contain cells of neural (N-type) and epithelial (substrate-adheren t, or S-type) phenotypes. Using isolated N-type and S-type cells from neuroblastoma, medulloblastoma, melanoma, and glioma cell lines, we de monstrate that the determinants of the response to DNA cleavage are in trinsic properties of the cell. Furthermore, using a series of analogu es of enediyne deoxyribonucleic acid (DNA) cleaving agents, we show th at the molecular target of these agents is likely to be the same in N- and S-type cells, implying that the difference in response characteri stics is a function of different distal pathways that are triggered by DNA cleavage. We demonstrate that the concentration of the DNA damagi ng agent used, and not the specific characteristics of the damage it p roduces, is the trigger for production of the cellular response. Respo nse type does not correlate with previously published values for expre ssion of the apoptosis modulators Bcl-2, Bcl-X(L), wildtype p53, or, i n medulloblastoma lines, p75.