INHIBITION OF DNA REPLICON INITIATION BY 4-NITROQUINOLINE 1-OXIDE, ADRIAMYCIN, AND ETHYLENEIMINE

Abstract

The effects of 3 widely differing chemical carcinogens, 4-nitroquinoline 1-oxide, adriamycin and ethylenemine on DNA replication in HeLa S3 cells were studied by pulse labeling of DNA with [3H]thymidine and sedimentation analysis with alkaline sucrose gradients. At doses that reduced the rate of DNA synthesis to 30-60% of control values, only ethyleneimine produced damage that resulted in lower MW or parental DNA. All 3 chemicals inhibited replicon initiation but to differing extents. Inhibition of replicon initiation was the first clearly identified effect of 4-nitroquinoline 1-oxide and was the main cause of inhibition of DNA synthesis. Ethyleneimine caused severe inhibition of replicon initiation but blocks to chain elongation also contributed significantly to the inhibition of overall DNA synthesis. Adriamycin affected replicon initiation to a small but significant extent; the primary cause of inhibition of DNA synthesis by this drug was a slowing of the rate of chain elongation. Inhibition of replicon initiation apparently is an important mechanism for the action of DNA-damaging agents in mammalian cells. Control of DNA replication may depend on the structural integrity of a chromosomal subunit that consists of several replicons.