Abstract
DNA damage induced in V79 cells by F 11782, or 2″,3″-bis pentafluorophenoxyacetyl-4′, 6′-ethylidene-β-D glucoside of 4′-phosphate- 4′-demethylepipodophyllotoxin 2N-methyl glucamine salt, a novel dual catalytic inhibitor of topoisomerases I and II, was investigated using both alkaline and neutral versions of the comet assay methodology. A comparison was then made of the DNA damage induced by F 11782 with that induced by either etoposide or camptothecin under comparable experimental conditions. The results revealed that F 11782 initially induced less DNA strand breaks that either etoposide or camptothecin and rejoined such breaks more slowly. However, unlike these other drugs, the extent of DNA damage induced by F 11782 increased linearly with time of incubation. F 11782 produced both DNA single- and double-strand breaks without any clear specificity relative to phase of the cell cycle, although proliferating cells were preferentially damaged. The marked time-dependency of induction of DNA strand breaks by F 11782 may serve to explain, at least in part, its major in vivo antitumour activities. © 2000 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Barret J-M, Montaudon D, Etiévant C, Baudouin C, Limouzy A, Cabrol N, Charvéron M, Robert J and Hill BT (1999) DNA damage induction and DNA repair inhibition by F 11782, a novel catalytic dual inhibitor of topoisomerases I and II. Proc Am Assoc Cancer Res 40: 761
Durand RE (1982) Use of Hoechst 33342 for cell selection of multicell systems. J Histochem Cytochem 30: 117–122
Etiévant C, Kruczynski A, Perrin D, Cabrol N, Cassabois V, Chansard N and Hill BT (1999) In vitro cytotoxic effects of F 11782, a novel catalytic dual inhibitor of topoisomerases I and II. Proc Am Assoc Cancer Res 40: 759
Guminski Y, Cugnasse S, Fabre V, Monse B, Kruczynski A, Etiévant C, Hill BT and Imbert T (1999) Synthesis and antitumor activity of a novel epipodophylloid: F 11782, a dual inhibitor of topoisomerases I and II. Proc Am Assoc Cancer Res 40: 4510
Klaude M, Eriksson S, Nygren J and Ahnström G (1996) The comet assay: mechanisms and technical considerations. Mutat Res 363: 89–96
Kruczynski A, Astruc J, Chazottes E, Ricome C, Berrichon G, Imbert T, Colpaert F and Hill BT (1999) Preclinical antitumor activity of F 11782, a novel catalytic dual inhibitor of topoisomerases I and II. Proc Am Assoc Cancer Res 40: 757
Ng S-W, Liu Y, Hasselblatt KT, Mok SC and Berkowitz RS (1999) A new human topoisomerase III that interacts with SGS1 protein. Nucleic Acids Res 27: 993–1000
Nitiss JL (1998) Investigating the biological functions of DNA topoisomerases in eukaryotic cells. Biochim Biophys Acta 1400: 63–81
Olive PL and Banáth JP (1993) Induction and rejoining of radiation-induced DNA single-strand breaks: “tail moment” as a function of position in the cell cycle. Mutat Res 294: 275–283
Olive PL, Banáth JP and Durand RE (1990) Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the ‘Comet assay’. Radiat Res 122: 86–94
Olive PL, Banáth JP and Evans HH (1993) Cell killing and DNA damage by etoposide in Chinese hamster V79 monolayers and spheroids: influence of growth kinetics, growth environment and DNA packaging. Br J Cancer 67: 522–530
Olive PL, Banáth JP and Durand RE (1997) Detection of subpopulations resistant to DNA-damaging agents in spheroids and murine tumours. Radiat Res 375: 157–165
Olive PL and Johnston PJ (1997) DNA damage from oxidants: influence of lesion complexity and chromatin organization. Oncol Res 9: 287–294
Perrin D, Kruczynski A, Barret J-M, Etiévant C, Chansard N, Gras S, Limouzy A, Rigaud S and Hill BT (1999) Biological characterization of the in vitro activities of F 11782, a novel catalytic dual inhibitor of topoisomerases I and II. Proc Am Assoc Cancer Res 40: 756
Perrin D, Van Hille B, Barret J-M, Kruczynski A, Etiévant C, Imbert T and Hill BT (2000) F 11782, a novel epipodophylloid non-intercalating dual catalytic inhibitor of topoisomerases I and II with an original mechanism of action. Biochem Pharmacol 59: 807–819
Sutherland RM (1988) Cell and environment interactions in tumor microregions: The multicell spheroids model. Science 240: 177–184
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Barret, JM., Hill, B. & Olive, P. Characterization of DNA-strand breakage induced in V79 cells by F 11782, a catalytic inhibitor of topoisomerases. Br J Cancer 83, 1740–1746 (2000). https://doi.org/10.1054/bjoc.2000.1514
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1054/bjoc.2000.1514
