Administration of 0.3 microM mitomycin C (MMC) or 2.0 microM cis-diamminedichloroplatinum II (CDDP) decreased the growth activity and induced the differentiation of U-937 human promonocytic cells, as shown by nitroblue tetrazolium reduction and an increase in surface expression of the leukocyte integrins CD11b/CD18 and CD11c/CD18. Expression of these differentiation markers started to be significant at 48 hr of treatment. These concentrations resulted in little cell damage (determined by Trypan blue exclusion) and slightly induced apoptosis (determined by DNA degradation and changes in nuclear morphology). The treatments induced a transient increase in c-fos and c-jun mRNA levels, with maximum values at 1-6 hr; a transient increase in collagenase mRNA level, with a maximum value at 48 hr; and a progressive increase in vimentin and lamin A and C mRNA levels. These changes were qualitatively similar to those produced by 12-0-tetradecanoylphorbol 13-acetate. CDDP and MMC also caused a transient increase of total AP-1 binding activity, as determined by gel retardation assays. The drugs produced an early transient activation (3-6 hr) of membrane-bound protein kinase C, followed by a later activation (48 hr) of both the membrane and the cytosolic enzyme. These results suggest that protein kinase C and AP-1-dependent gene expression could be involved in myeloid cell differentiation by alkylating agents.