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On a Possible Relationship of Cyclic AMP to the Mechanism of Action of Nerve Growth Factor

1972; SAGE Publishing; Volume: 140; Issue: 1 Linguagem: Inglês

10.3181/00379727-140-36392

1535-3702

David C. Haas, Daniel B. Hier, B. G. W. Arnason, Marian F. Young,

Cancer Research and Treatments

Several recent studies have shown that N6, O2-dibutyryl-3',5'-cyclic adenosine monophosphate (dibutyryl cyclic AMP) can transform cells of various tumor lines so that they take on a more normal structural appearance. The initial observations were made by Hsie and Puck (1) using Chinese hamster ovarian tumor cells and by Johnson, Friedman, and Pastan (2) using rat sarcoma and neoplastic mouse fibroblast lines. Similar observations have been made with tumors of nervous tissue origin. For example, morphologic changes in glioblastoma cells under the influence of dibutyryl cyclic AMP have been reported by Perkins and MacIn-tyre (3), and neuroblastoma cells have been shown to differentiate, as judged by neurite extension, following exposure to dibutyryl cyclic AMP (4, 5). An effect of dibutyryl cyclic AMP on the morphology of nonneoplastic mammalian nervous tissue has not yet been reported. The studies presented below reveal that treatment of fetal mammalian sensory ganglia with dibutyryl cyclic AMP produces increased neurite outgrowth and that this outgrowth mimics that observed in cultures exposed to nerve growth factor (NGF). After the work reported here was completed, we learned that Roisen et al. (6) had made similar observations with chick embryo ganglia. Methods. Gasserian ganglia from rat or mouse fetuses, 17-19 days in utero, were placed on collagen-coated coverslips in Max-imow double coverslip assemblies, as described earlier (7). A drop of F-10 feeding medium (Gibco) containing 25% fetal calf serum and 750 mg of glucose/100 ml was added, and the cultures were incubated at 35° for 24 hr. Dibutyryl cyclic AMP (Sigma) was prepared as a 50 mM stock solution in F-10, frozen in aliquots, and thawed and diluted for use as needed. All growth media containing dibutyryl cyclic AMP contained fetal calf serum and glucose at the concentrations given above.