Interactions of antitumor triazoloacridinones with DNA.
Triazoloacridinones (TA) are a new group of potent antitumor compounds, from which the most active derivative, C-1305, has been selected for extended preclinical trials. This study investigated the mechanism of TA binding to DNA. Initially, for selected six TA derivatives differing in chemical structures as well as cytotoxicity and antitumor activity, the capability of noncovalent DNA binding was analyzed. We showed that all triazoloacridinones studied stabilized the DNA duplex at a low-concentration buffer but not at a salt concentration corresponding to that in cells. DNA viscometric studies suggested that intercalation to DNA did not play a major role in the mechanism of the cytotoxic action of TA. Studies involving cultured cells revealed that triazoloacridinone C-1305 after previous metabolic activation induced the formation of interstrand crosslinks in DNA of some tumor and fibroblast cells in a dose dependent manner. However, the detection of crosslink formation was possible only when the activity of topoisomerase II in cells was lowered. Furthermore, it was impossible to validate the relevance of the ability to crosslink DNA to biological activity of TA derivatives.
Koba
Marcin
M
Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, Gdańsk, Poland.
Konopa
Jerzy
J
D000166:Acridines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D054831:Acridones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D003432:Cross-Linking Reagents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D009690:Nucleic Acid Conformation / Q000187:drug effects; D014230:Triazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
D000166:Acridines; D054831:Acridones; D000970:Antineoplastic Agents; C488734:C 1305; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D014230:Triazoles; D004247:DNA