TOPOISOMERASE II AND DRUG RESISTANCE IN ACUTE LEUKEMIA

Project: Research project

Project Details

Description

Despite dramatic advances in chemotherapy, over 50% of all adults
who develop acute myelogenous leukemia (AML) die with recurrent or
refractory disease. Further improvements in the treatment of this
disorder depend in part in understanding at a cellular level why
some patients achieve sufficient tumor kill to eradicate their
tumor and others receiving the same therapy do not. Recent studies
suggest that several agents used to treat AML act by stabilizing
a covalent adduct between the nuclear enzyme topoisomerase II (topo
II) and genomic DNA, thus creating protein linked DNA strand
breaks. Current therapy of newly diagnosed AML at this institution
utilizes two topo II directed agents (daunorubicin and amsacrine)
in combination with cytosine arabinoside. To assess the
possibility that differences in topo 11 might be related to the
success or failure of this therapy. A prospective study of topo
II levels in clinical samples of blasts from adults with AML was
undertaken. Topo II levels (assessed by Western blotting) varied
at least lO fold from patient to patient. Significantly, patients
whose blasts had high levels of topo II had a much lower
probability of achieving complete remission. Proposed studies
utilizing Northern and Southern blot analysis are designed to
elucidate the mechanism of variation in copo II levels between
blasts from different patients. Additional experiments will
prospectively assess 1) the effect of topo II directed agents on
the clonogenicity of patients' leukemic blasts in vitro, 2) the
ability of topo ll directed agents to stabilize topo ll DNA adducts
in intact blasts and isolated nuclei, and 3) the transport of topo
II-directed agents into leukemic blasts. These studies should
provide insight into the mechanisms of resistance of adult AML to
topo II-directed chemotherapeutic agents and give direction to
future clinical trials of methods to overcome this resistance.
StatusFinished
Effective start/end date6/1/895/31/93

Funding

  • National Institutes of Health: $164,750.00
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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