THE MODE OF ACTION OF CYTO-TOXIC AND ANTITUMOR 1-NITROACRIDINES .4. CYTO-TOXIC AND ANTITUMOR-ACTIVITY OF 1-NITROACRIDINES AS AN AFTEREFFECT OF THEIR INTERSTRAND DNA CROSS-LINKING
- 1 January 1984
- journal article
- research article
- Vol. 44 (10) , 4289-4296
Abstract
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, the cross-linking potency of the derivatives with structural modifications in position 9 of the acridine nucleus was estimated at their in vitro threshold concentrations (0.3-4.5 .mu.m), beyond which the 1st 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 (3-1065 .mu.mol/kg of body weight), as well as their in vitro cytotoxicity against cultured HeLa or HeLa S3 cells (0.0005-7.2 .mu.m), indicating that the interstrand DNA cross-linking potency might be 1 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, because no significant differences were observed among the agents with respect to their polarographic half-wave potentials estimated under anaerobic conditions.This publication has 8 references indexed in Scilit:
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