C-jun mRNA and AP-1 levels were examined in etoposide (VP-16)-sensitive (K562) and -resistant (K/VP.5) human leukemia cell lines. Previously, we reported that K/VP.5 cells have increased basal levels of mRNA for the protooncogene c-jun (Ritke MK and Yalowich JC, Biochem Pharmacol 46: 2007-2020, 1993). In this study, we show that the 3-fold increase in c-jun transcripts in K/VP.5 cells was accompanied by a 2-fold increase in the stability of the mRNA for this gene and a nearly 2-fold increase in AP-1 DNA binding activity compared with parental K562 cells. Treatment of K562 and K/VP.5 cells with 50-200 microM VP-16 resulted in 3- to 10-fold stimulation of c-jun transcripts, which peaked 90-150 min after addition of drug and remained elevated up to 5 hr. In contrast, amsacrine stimulated the levels of c-jun mRNA only 3-fold in both cell lines, and its c-jun stimulatory effects were decreased at concentrations greater than 50 microM. VP-16 stimulation of c-jun mRNA levels resulted in a 2-fold increase in AP-1 binding activity in K562 but not in K/VP.5 cells. Taken together, these results suggest that posttranscriptional changes in c-jun mRNA regulation may be associated with acquired resistance to VP-16.