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Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in
human leukemia cells
SH Kaufmann, PA Svingen, SD Gore, DK Armstrong, YC Cheng and EK Rowinsky
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
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
micromol/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 micromol/L (median, 30 micromol/ 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.
Volume 89,
Issue 6,
pp. 2098-2104,
03/15/1997
Copyright © 1997 by The American Society of Hematology
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