Analysis of topoisomerase I/DNA complexes in patients administered topotecan
- PMID: 7743509
Analysis of topoisomerase I/DNA complexes in patients administered topotecan
Abstract
As part of a Phase II clinical trial of topotecan, DNA breakage in vivo was measured by detecting covalent topoisomerase/DNA intermediates in peripheral blood. The ICE (in vivo complex of enzyme) bioassay was used to assess topotecan activity in the peripheral blood of patients before, during, and after infusion therapy. The results can be summarized as: (a) ICE bioassay is a specific, antibody-based assay for topoisomerase I-mediated DNA damage. Topoisomerase I/DNA complex formation can be monitored unambiguously in the absence of topotecan to establish a basal level of endogenous enzyme action on DNA; (b) infusion of topotecan significantly stimulated formation of covalent enzyme/DNA complexes. Complexes were detected within 5 min postinfusion and increased over the course of a 30-min treatment; (c) after termination of infusion, complex formation decreased by 3-4-fold within 30 min, showing that cleavage complexes quickly reseal after drug withdrawal; and (d) formation of complexes varied widely between patients. The ICE bioassay can evaluate the effects of topoisomerase I inhibitors on target tissues; thus, it may valuable in predicting response to these drugs.
Similar articles
-
Liposomal encapsulation increases the activity of the topoisomerase I inhibitor topotecan.Oncol Res. 1995;7(9):461-9. Oncol Res. 1995. PMID: 8835290
-
Intermittent exposure of medulloblastoma cells to topotecan produces growth inhibition equivalent to continuous exposure.Clin Cancer Res. 1997 Oct;3(10):1731-8. Clin Cancer Res. 1997. PMID: 9815557
-
Pharmacodynamics of topoisomerase I inhibition: Western blot determination of topoisomerase I and cleavable complex in patients with upper gastrointestinal malignancies treated with topotecan.Clin Cancer Res. 1998 Mar;4(3):545-57. Clin Cancer Res. 1998. PMID: 9533521 Clinical Trial.
-
Efficacy and safety of topotecan in the treatment of advanced ovarian carcinoma.Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-19-S5-25. Semin Oncol. 1997. PMID: 9122738 Review.
-
[Poisons of DNA topoisomerases I and II].Bull Cancer. 1993 Nov;80(11):923-54. Bull Cancer. 1993. PMID: 8081034 Review. French.
Cited by
-
The topoisomerase IIbeta circular clamp arrests transcription and signals a 26S proteasome pathway.Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3239-44. doi: 10.1073/pnas.0736401100. Epub 2003 Mar 10. Proc Natl Acad Sci U S A. 2003. PMID: 12629207 Free PMC article.
-
Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development.Br J Cancer. 1997;76(7):952-62. doi: 10.1038/bjc.1997.491. Br J Cancer. 1997. PMID: 9328159 Free PMC article. Review.
-
Induction of topoisomerase I cleavage complexes by 1-beta -D-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells.Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1885-90. doi: 10.1073/pnas.97.4.1885. Proc Natl Acad Sci U S A. 2000. PMID: 10677551 Free PMC article.
-
Hyperphosphorylation of RNA polymerase II in response to topoisomerase I cleavage complexes and its association with transcription- and BRCA1-dependent degradation of topoisomerase I.J Mol Biol. 2008 Sep 5;381(3):540-9. doi: 10.1016/j.jmb.2008.06.028. Epub 2008 Jun 17. J Mol Biol. 2008. PMID: 18588899 Free PMC article.
-
Contributions of the D-Ring to the activity of etoposide against human topoisomerase IIα: potential interactions with DNA in the ternary enzyme--drug--DNA complex.Biochemistry. 2011 Jun 7;50(22):5058-66. doi: 10.1021/bi200531q. Epub 2011 May 13. Biochemistry. 2011. PMID: 21548574 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Other Literature Sources
Medical
Research Materials