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 µm), 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 < 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 µmol/kg of body weight), as well as their in vitro cytotoxicity against cultured HeLa or HeLa S3 cells (0.0005 to 7.2 µm), 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.

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Supported by Grant PR-6/1704 from the Polish National Cancer Program, continued by Jerzy Konopa, Ph.D., and associates at the Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, Majakowskiego 11/12, 80-952 Gdansk 6, Poland. A preliminary communication of part of this work was presented at the 17th Meeting of the Polish Biochemical Society, September 11 to 13, 1980, Warsaw, Poland (Abstract), and at the 13th International Cancer Congress, September 8 to 15, 1982, Seattle, WA. This is Paper 4 in a series on “The Mode of Action of Cytotoxic and Antitumor 1-Nitroacridines.”

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