Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells

Scott H. Kaufmann, Phyllis A. Svingen, Steven D. Gore, Deborah K. Armstrong, Yung Chi Cheng, Eric K. Rowinsky

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Topotecan (TPT) is a topoisomerase I (topo I) poison that has shown promising antineoplastic activity in solid tumors and acute leukemia. In the present study, a band depletion assay was used to evaluate the ability of TPT to stabilize topo I-DNA adducts in human leukemia cell lines and in clinical leukemia samples ex vivo. This assay showed that 50% of the cellular topo I in HL-60 human myelomonocytic leukemia cells became covalently bound to DNA at an extracellular TPT concentration of 4 μmol/L. In contrast, in 13 clinical specimens of human leukemia harvested before treatment of patients with TPT, the TPT concentration required to stabilize 50% of the cellular topo I in topo I-DNA complexes ranged from 3 to greater than 100 μmol/L (median, 30 μmol/L). Flow microfluorimetry showed that cellular TPT accumulation varied over only a twofold range and failed to provide evidence for transport-mediated resistance in the clinical samples. These observations raise the possibility that formation of topo I-DNA adducts is diminished in many specimens of refractory/relapsed acute leukemia by a mechanism that might alter topo I sensitivity to TPT.

Original languageEnglish (US)
Pages (from-to)2098-2104
Number of pages7
JournalBlood
Volume89
Issue number6
DOIs
StatePublished - Mar 15 1997

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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