DIFFERENTIAL INHIBITION OF THE DNA-BINDING OF TRANSCRIPTION FACTORS NF-KAPPA-B AND OTF-1 BY NITROGEN-MUSTARD AND QUINACRINE MUSTARD - TRANSCRIPTIONAL IMPLICATIONS

Nitrogen mustard (HN2) and quinacrine mustard (QM) both inhibited the binding of NFkappaB to the GC-rich consensus sequence in the HIV long terminal repeat (LTR), as assessed by gel-shift assays. QM also inhibi ted the binding of OTF-1 to the AT-rich octamer present in the H2B pro moter whereas HN2 was inactive. Inhibition of the binding of transcrip tion factors was due to the drug interaction with DNA, since it also o ccurred when transcription factors were added to DNA after removal of free drug. In Jurkat cells transfected with pI3CAT, where the chloramp henicol acetyltransferase (CAT) gene is under the control of the HIV L TR, both HN2 and QM inhibited CAT gene expression. However, in Jurkat cells transfected with plasmid - 147, where the CAT gene is under the control of the H2B promoter, QM inhibited CAT expression but HN2 did n ot. These results were obtained at concentrations of HN2 or QM that in hibited total DNA and RNA synthesis to a similar extent. The present r esults suggest that the more selective pharmacological activity of HN2 (HN2 is an active antineoplastic agent whereas QM is inactive and ver y toxic) might be related to its preferential functional inhibition of GC-rich consensus sequence, possibly important in the regulation of g enes involved in the malignant proliferation and behavior of some tumo rs.