Inhibition of the initiation of leukemic transcription by N-trifluoroacetyladriamycin-14-O-hemiadipate in vitro. Impaired formation of RNA polymerase-DNA complex.

Abstract

The effect of N-trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), a new derivative of adriamycin, on various steps of the enzymic reaction catalyzed by chicken myeloblastosis RNA polymerase II was studied. AD 143 inhibition of RNA synthesis, which was evident at the beginning of the reaction, could not be reversed by increasing the concentrations of any one of the four nucleoside triphosphate substrates of the reaction. Furthermore, the RNA synthesis inhibition was not affected by varying the concentrations of template DNA. The AD 143-induced inhibition caused a reduction of the frequency of RNA chain initiation, whereas the average chain length of RNA synthesized at the end of the reaction remained unaltered. The susceptible step in the initiation process was found to be the formation of stable complexes between RNA polymerase and the DNA template. While AD 143 causes no inhibition of Escherichia coli RNA polymerase activity, it was found not to affect the E. coli RNA polymerase-template DNA complex formation.