The mechanism of inhibition of DNA replication in HeLa S3 cells by the antitumor drug Ledakrin and other antitumor 1-nitro-9-aminoacridines.
These studies were aimed at characterizing the capability of an antitumor DNA-damaging drug, Ledakrin, and its analogs to inhibit DNA replication in HeLa S3 cells. The studied agents are extremely potent inhibitors of [3H]thymidine incorporation in whole cells. These compounds produced also a potent dose- and time-dependent inhibition of DNA synthesis in subcellular systems derived from drug-treated cells, as found by [3H]dGTP incorporation in cellular lysates and nuclei. Experiments in which nuclei from control and drug-treated cells were supplemented with cytoplasmic fractions from either control or drug-treated cells, or with exogenous DNA, demonstrate that Ledakrin and other 1-nitro-9-aminoacridines inhibit DNA replication in HeLa S3 cells by interfering with the DNA template, while not affecting DNA polymerase(s) or other enzymes and replication factors. The negligible effect of Ledakrin added to lysates or nuclei from untreated cells suggests that metabolic activation is a prerequisite for replication inhibition by Ledakrin. Analysis of the size of newly synthesized DNA, by alkaline sucrose gradient sedimentation, indicates that Ledakrin does not inhibit the initiation of replication but does interfere with chain growth. Impairment of DNA replication by 1-nitro-9-aminoacridines seems to originate from DNA damage and to result in the inhibition of cellular growth.
D000609:Aminoacridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002458:Cell Fractionation; D004261:DNA Replication / Q000187:drug effects*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008970:Molecular Weight; D009564:Nitracrine / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism
D000609:Aminoacridines; D000970:Antineoplastic Agents; D003848:Deoxyguanine Nucleotides; D009564:Nitracrine; C029603:deoxyguanosine triphosphate; D013936:Thymidine