Inhibition of DNA and RNA synthesis by daunorubicin in sensitive and resistant Ehrlich ascites tumor cells in vitro.

Abstract

The effect of daunorubicin (DNR) on nucleic acid synthesis was investigated in vitro in cells from an Ehrlich ascites tumor that was sensitive in vivo to DNR and in cells from a subline of the tumor in which resistance to DNR had been developed in vivo . DNR inhibited DNA and RNA synthesis in sensitive as well as in resistant cells, as determined from the incorporation of three different radioactive precursors. In order to give the same degree of inhibition of DNA and RNA synthesis in resistant cells as in sensitive cells, the DNR concentrations required were approximately 5 times greater. When the synthesis of different RNA species in sensitive cells was analyzed, nucleoplasmic heterodisperse RNA was found to be the least DNR sensitive, while tRNA, 5 S RNA, and two small-molecular-weight RNA components had a medium sensitivity to DNR. Labeling of rRNA and of the 45 S and 32 S nucleolar RNA was found to be inhibited most and to the same extent, indicating that it is the synthesis of 45 S RNA that is inhibited and not the processing of 45 S RNA to rRNA. The preferential inhibition of rRNA was less pronounced in resistant cells than in sensitive cells, thus indicating that the sensitivity of rRNA synthesis was changed more during development of resistance than was the sensitivity of synthesis of other RNA components. The cellular uptake of DNR was less in resistant than in sensitive cells, but the difference was too small to explain the differences in inhibition of the nucleic acid synthesis.