De-regulation of c-myc by chromosomal translocation is one crucial step for the development of Burkitt's lymphoma. The de-regulation is caused through juxtaposition of c-myc with one of the 3 immunoglobulin loci. We have reported earlier that treatment of Burkitt's lymphoma cells with n-butyrate causes transcriptional down-regulation of c-myc expression. Because of the possible therapeutic implication of this result, we looked for other compounds which, on the one hand, might be applicable in vivo and, on the other hand, might cause down-regulation of c-myc expression in Burkitt's lymphoma cells. Since n-butyrate is known to induce differentiation, we have examined other differentiation inducers of different chemical nature for their ability to reduce c-myc expression in Burkitt's lymphoma cells. Many of the substances tested caused down-regulation of c-myc expression, which, however, was transient except for n-butyrate. Three types of compounds proved to be particularly active: polar planar compounds (e.g., dimethylsulfoxide), heterocyclic compounds (e.g., hypoxanthine), and short-chain fatty acids (e.g., n-butyric acid). The action of n-butyrate on c-myc supression was exceptional not only in not being transient, but also in being allele-specific: it down-regulated the translocated allele without affecting the normal one. Medium transfer experiments revealed that neither degradation of the active compound nor an intracellular resistance mechanism can fully account for the reversibility of c-myc down-regulation after treatment with the transiently acting polar planar compounds. © 1995 Wiley-Liss, Inc.