Cytotoxic and antitumor activity of 1-nitroacridines as an aftereffect of their interstrand DNA cross-linking.
To determine whether the toxic effects and changes in many cell functions caused by antitumor 1-nitroacridines are related to their enzymatically mediated covalent interstrand DNA cross-linking (J. Konopa, J. W. Pawlak, and K. Pawlak. Chem.-Biol. Interact., 43: 175-197, 1983), the cross-linking potency of the derivatives with structural modifications in position 9 of the acridine nucleus was estimated as their in vitro threshold concentrations (0.3 to 4.5 microM), beyond which the first interstrand DNA cross-links could be detected in DNA of cultured HeLa S3 cells with a polyethylene glycol 6000-Dextran T500 assay. Statistically significant (p less than 0.05) correlations exist between the cross-linking potency of 1-nitroacridines and their in vivo antitumor activity and toxicity against mice with Sarcoma 180 tumors in solid form (3 to 1065 mumol/kg of body weight), as well as their in vitro cytotoxicity against cultured HeLa or HeLa S3 cells (0.0005 to 7.2 microM), indicating that the interstrand DNA cross-linking potency might be one of primary determinants of in vivo and in vitro biological activity of 1-nitroacridine antineoplastic drugs. Susceptibility of the parent agents to reduction does not appear to be a rate-limiting factor of DNA cross-linking potency of 1-nitroacridines and their metabolic transformations (J. W. Pawlak, and J. Konopa. Biochem. Pharmacol., 28: 3391-3402, 1979), because no significant differences were observed among the agents with respect to their polarographic half-wave potentials estimated under anaerobic conditions.
D000166:Acridines / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004273:DNA, Neoplasm / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D009574:Nitro Compounds / Q000627:therapeutic use / Q000633:toxicity; D010084:Oxidation-Reduction; D012510:Sarcoma 180 / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000166:Acridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009574:Nitro Compounds