PREVENTION OF NEOCARZINOSTATIN-INDUCED CELL-DEATH AND MORPHOLOGIC CHANGE IN SK-N-SH HUMAN NEUROBLASTOMA-CELLS BY CONTINUOUS EXPOSURE TO NERVE GROWTH-FACTOR

Neocarzinostatin is an antineoplastic agent that induces differentiate d morphology in human (SK-N-SH) neuroblastoma cells in culture. We hav e compared this morphological differentiation with that induced by the endogenous differentiation inducer, nerve growth factor (NGF), and ha ve explored the effects of exposure to NGF upon the morphological chan ges induced by neocarzinostatin in SK-N-SH cells. Both NGF and neocarz inostatin induced process outgrowth in these cells. The processes form ed in the presence of NGF however, were shorter and thinner than those induced by neocarzinostatin. Furthermore, only neocarzinostatin induc ed enlargement of the somata of the cells. and caused cell death in a concentration-dependent fraction of the culture. These distinguishing features of treated cells allowed us to determine whether or not NGF e xposure altered responsiveness of the cells to neocarzinostatin. NGF ( 100-1000 ng/mL) protected SK-N-SH cells from the morphological and cyt ocidal effects of neocarzinostatin (1-hr exposure, 0.017 to 0.033 mug/ mL). Protection from neocarzinostatin required that NGF be continuousl y present for a period beginning 24 hr prior to neocarzinostatin expos ure and continuing for the duration of the experiment, implying that t he protection afforded by NGF has a latency necessitating pretreatment , and is reversible. These results suggest that neocarzinostatin is ta ken up by the cells and can exert its effects once NGF is removed, eve n after neocarzinostatin is washed out of the medium. The signal trans duction cascade triggered by NGF receptor binding may prevent the acti on of neocarzinostatin or the expression of the cellular changes induc ed in SK-N-SH cells by neocarzinostatin.