||Polyploidy Induction as a Consequence of Topoisomerase Inhibition. A Flow Cytometric Assessment.
Zucker, R. M. ;
Adams, D. J. ;
Bair, K. W. ;
Elstein, K. H. ;
||ManTech Environmental Technology, Inc., Research Triangle Park, NC. ;Northrop Services, Inc., Research Triangle Park, NC. ;Burroughs Wellcome Co., Research Triangle Park, NC.;Health Effects Research Lab., Research Triangle Park, NC.
DNA topoisomerase II ;
Enzyme inhibitors ;
Acute erythroblastic leukemia ;
Cell cycle ;
Dose-response relationships ;
Deoxyribonucleic acids ;
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||Following recovery from a 4-h exposure to clinically achievable concentrations of the topoisomerase II inhibitors Adriamycin, teniposide, or amsacrine or the putative topoisomerase II inhibitor crisnatol, murine erythroleukemic cells remained viable for up to 48 hr, but did not proliferate. Cell cycle analysis after a 24-hr recovery revealed blocks in G2 (4N DNA) or >G2 (up to 8N DNA) polyploid stages. The relative percentages of cells in either stage was a function of drug concentration and cell cycle stage at time of exposure: typically, cells exposed during S phase became blocked in G2, whereas those exposed during G2/M progressed into >G2 polyploid stages. G2-blocked cells exhibited a 2- to 3-fold increase in nuclear protein content and cellular/nuclear volume (i.e. unbalanced growth) and about 5% more DNA stainability (as a consequence of nuclear conformational changes rather than redundant DNA synthesis). In all cases, at the drug concentrations studied, mitotic figures were absent and G2 and >G2 blocks were irreversible, indicating that the mechanism of polyploidy induction differs from that of microtubule inhibitors. These findings suggest that although topoisomerase inhibitors interfere with DNA synthesis in the S phase, their induction of >G2 polyploid blocks may involve direct or indirect inhibition of chromosome condensation. (Copyright (c) 1991. Pergamon Press plc.)
||Pub. in Biochemical Pharmacology, v42 n11 p2199-2208 Nov 91. See also PB92-110451. Prepared in cooperation with Northrop Services, Inc., Research Triangle Park, NC., and Burroughs Wellcome Co., Research Triangle Park, NC. Sponsored by Health Effects Research Lab., Research Triangle Park, NC.
|NTIS Title Notes
||Reprint: Polyploidy Induction as a Consequence of Topoisomerase Inhibition. A Flow Cytometric Assessment.
||PC A03/MF A01