|
|
 Previous Article | Table of Contents | Next Article 
Topoisomerase II levels and drug sensitivity in adult acute myelogenous
leukemia
SH Kaufmann, JE Karp, RJ Jones, CB Miller, E Schneider, LA Zwelling, K Cowan, K Wendel and PJ Burke
Oncology Center, Johns Hopkins Hospital, Baltimore, MD.
The topoisomerase (topo) II-directed agents etoposide, daunorubicin (DNR),
and amsacrine (m-AMSA) are widely used in the treatment of acute
myelogenous leukemia (AML). In the present study, multiple aspects of topo
II-mediated drug action were examined in marrows from adult AML patients.
Colony-forming assays revealed that the dose of etoposide, DNR, or m-AMSA
required to diminish leukemic colony formation by 90% (LD90) varied over a
greater than 20-fold range between different pretreatment marrows.
Measurement of nuclear DNR accumulation in the absence and presence of
quinidine revealed evidence of P-glycoprotein (Pgp) function in 8 of 82
samples at diagnosis and 5 of 36 samples at first relapse, but the largest
quinidine-induced increment in DNR accumulation (< 2-fold) was too small
to explain the variations in drug sensitivity. Restriction enzyme-based
assays and sequencing of partial topo II alpha and topo II beta cDNAs from
the most highly resistant specimens failed to demonstrate topo II gene
mutations that could account for resistance. Western blotting of marrow
samples containing greater than 80% blasts revealed that the content of the
two topo II isoenzymes varied over a greater than 20-fold range, but did
not correlate with drug sensitivity in vitro or in vivo. In addition,
levels of topo II alpha and topo II beta in 46 of 47 clinical samples were
lower than in human AML cell lines. Immunoperoxidase staining showed that
these low topo II levels were accompanied by marked cell-to- cell
heterogeneity, with topo II alpha being abundant in some blasts and
diminished or absent from others. There was a trend toward increasing
percentages of topo II alpha-positive cells in pretreatment marrows that
contained more S-phase cells. Consistent with this observation, treatment
of patients with granulocyte-macrophage colony- stimulating factor for 3
days before chemotherapy resulted in increases in topo II alpha-positive
cells concomitant with increases in the number of cells traversing the cell
cycle. These observations have implications for the regulation of topo II
in AML, for the use of topo II-directed chemotherapy, and for future
attempts to relate drug sensitivity to topo II levels in clinical material.
Volume 83,
Issue 2,
pp. 517-530,
01/15/1994
Copyright © 1994 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A J Lodge, A G Hall, M M Reid, G G McIntosh, M Steward, J J Anderson, C H W Horne, and B Angus
Topoisomerase II{{alpha}} and II{beta} expression in childhood acute lymphoblastic leukaemia: relation to prognostic factors and clinical outcome
J. Clin. Pathol.,
January 1, 2001;
54(1):
31 - 36.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Svingen, J. E. Karp, S. Krajewski, P. W. Mesner Jr, S. D. Gore, P. J. Burke, J. C. Reed, Y. A. Lazebnik, and S. H. Kaufmann
Evaluation of Apaf-1 and procaspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia
Blood,
December 1, 2000;
96(12):
3922 - 3931.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. U. Kurz, K. B. Leader, D. J. Kroll, M. Clark, and F. Gieseler
Modulation of Human DNA Topoisomerase IIalpha Function by Interaction with 14-3-3epsilon
J. Biol. Chem.,
April 28, 2000;
275(18):
13948 - 13954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Svingen, A. Tefferi, T. J. Kottke, G. Kaur, V. L. Narayanan, E. A. Sausville, and S. H. Kaufmann
Effects of the bcr/abl Kinase Inhibitors AG957 and NSC 680410 on Chronic Myelogenous Leukemia Cells in Vitro
Clin. Cancer Res.,
January 1, 2000;
6(1):
237 - 249.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
A.-M. C. Dingemans, M. A. Witlox, R. A. L. M. Stallaert, P. van der Valk, P. E. Postmus, and G. Giaccone
Expression of DNA Topoisomerase II{{alpha}} and Topoisomerase II{beta} Genes Predicts Survival and Response to Chemotherapy in Patients with Small Cell Lung Cancer
Clin. Cancer Res.,
August 1, 1999;
5(8):
2048 - 2058.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. D. Kravtsov, J. P. Greer, J. A. Whitlock, and M. J. Koury
Use of the Microculture Kinetic Assay of Apoptosis to Determine Chemosensitivities of Leukemias
Blood,
August 1, 1998;
92(3):
968 - 980.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.M. Bond, P. Bonelli, M. Mesuraca, V. Agosti, C. Masone, C. Cuomo, A. Nisticò, P. Tassone, F. Tuccillo, L. Cecco, et al.
Identification by Differential Display of Transcripts Regulated during Hematopoietic Differentiation
Stem Cells,
March 1, 1998;
16(2):
136 - 143.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. H. Kaufmann, J. E. Karp, P. A. Svingen, S. Krajewski, P. J. Burke, S. D. Gore, and J. C. Reed
Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time of Leukemic Relapse
Blood,
February 1, 1998;
91(3):
991 - 1000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Kaufmann, P. A. Svingen, S. D. Gore, D. K. Armstrong, Y.-C. Cheng, and E. K. Rowinsky
Altered Formation of Topotecan-Stabilized Topoisomerase I-DNA Adducts in Human Leukemia Cells
Blood,
March 15, 1997;
89(6):
2098 - 2104.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
