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 journalArticle

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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
StatePublished - Mar 15 1997

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Topotecan
Type I DNA Topoisomerase
DNA Adducts
Leukemia
Assays
Poisons
Antineoplastic Agents
Refractory materials
Tumors
Flow Cytometry
Cells
Cell Line
DNA

ASJC Scopus subject areas

  • Hematology

Cite this

Kaufmann, S. H., Svingen, P. A., Gore, S. D., Armstrong, D. K., Cheng, Y. C., & Rowinsky, E. K. (1997). Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. Blood, 89(6), 2098-2104.

Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. / Kaufmann, Scott H; Svingen, Phyllis A.; Gore, Steven D.; Armstrong, Deborah K.; Cheng, Yung Chi; Rowinsky, Eric K.

In: Blood, Vol. 89, No. 6, 15.03.1997, p. 2098-2104.

Research output: Contribution to journalArticle

Kaufmann, SH, Svingen, PA, Gore, SD, Armstrong, DK, Cheng, YC & Rowinsky, EK 1997, 'Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells', Blood, vol. 89, no. 6, pp. 2098-2104.
Kaufmann SH, Svingen PA, Gore SD, Armstrong DK, Cheng YC, Rowinsky EK. Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. Blood. 1997 Mar 15;89(6):2098-2104.
Kaufmann, Scott H ; Svingen, Phyllis A. ; Gore, Steven D. ; Armstrong, Deborah K. ; Cheng, Yung Chi ; Rowinsky, Eric K. / Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. In: Blood. 1997 ; Vol. 89, No. 6. pp. 2098-2104.
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