The effects of retinoic acid on the in vitro and in vivo growth of neuroblastoma cells

Abstract

In large part, malignancy is the end result of aberrant cell growth and differentiation. Control of these processes is anticipated to result in a suppression of oncogenicity. Retinoic acid (RA), a derivative of vitamin A, has been shown to inhibit proliferation, induce cell differentiation and reverse the malignant phenotype of a variety of tumor cell types. In order to further characterize antitumor potential of RA, this study examined the in vitro and in vivo effects of this retinoid on cell lines derived from human neuro blastoma (NB). The in vitro phase of this study tested the ability of various compounds to raise intracellular cyclic adenosine 31:51 - monophosphate (cAMP) levels and either alone or in combination with RA-resistant cell lines. Direct activation of klthe synthetic enzyme adenylate cyclase by forskolin or cholera toxin increased intracellular cAMP levels remained elevated 2- to 7-fold above control values and were accompanied by a decrease in cell proliferation and an increase in cell differentiation. All these effects were exaggerated in lthe presence of phosphodiesterase inhibitors. Isoproterenol and epinephrine did not lalter cAMP levels and had no discernible biological effects. RA promoted differentiation with little effect on cAMP levels. Combination treatment of cells with RA plus agent treatment. From these data, it was concluded that: 1. the cAMP synthetic and degrada6tive pathways are functional in the NB cell lines studied; 2. elevation of cAMP is a sufficient but not necessary condition for inhibiting proliferation and promoting differentiation in lthese cells; 3. elevation of intracellular cAMP potentiates the differentiation-inducing activity of RA; and 4. overcoming retinoid resistance in some tumor cell lines may be feasible by alterations in the cAMP system. This would be of particular value in treating tumors that have lost retinoid responsiveness. © The American Laryngological, Rhinological & Otological Society, Inc.