DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition.
TAS-103 is a novel anticancer drug that kills cells by increasing levels of DNA cleavage mediated by topoisomerase II. While most drugs that stimulate topoisomerase II-mediated DNA scission (i.e., topoisomerase II poisons) also inhibit the catalytic activity of the enzyme, they typically do so only at concentrations above the clinical range. TAS-103 is unusual in that it reportedly inhibits the catalytic activity of both topoisomerase I and II and does so at physiologically relevant concentrations [Utsugi, T., et al. (1997) Jpn. J. Cancer Res. 88, 992-1002]. Without a topoisomerase activity to relieve accumulating torsional stress, the DNA tracking systems that promote the action of TAS-103 as a topoisomerase II poison would be undermined. Therefore, the effects of TAS-103 on the catalytic activity of topoisomerase I and II were characterized. DNA binding and unwinding assays indicate that the drug intercalates into DNA with an apparent dissociation constant of approximately 2.2 microM. Furthermore, DNA strand passage assays with mammalian topoisomerase I indicate that TAS-103 does not inhibit the catalytic activity of the type I enzyme. Rather, the previously reported inhibition of topoisomerase I-catalyzed DNA relaxation results from a drug-induced alteration in the apparent topology of the nucleic acid substrate. TAS-103 does inhibit the catalytic activity of human topoisomerase IIalpha, apparently by blocking the DNA religation reaction of the enzyme. The lack of inhibition of topoisomerase I catalytic activity by TAS-103 explains how the drug is able to function as a topoisomerase II poison in treated cells.
Fortune
J M
JM
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Velea
L
L
Graves
D E
DE
Utsugi
T
T
Yamada
Y
Y
Osheroff
N
N
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000634:Aminoquinolines / Q000494:pharmacology*; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004271:DNA, Fungal / Q000187:drug effects / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D010957:Plasmids / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000634:Aminoquinolines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004271:DNA, Fungal; D004278:DNA, Superhelical; D004268:DNA-Binding Proteins; D007192:Indenes; D007364:Intercalating Agents; D007527:Isoenzymes; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000251:Adenosine Triphosphatases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one