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

被引:55
作者
Kaufmann, SH
Svingen, PA
Gore, SD
Armstrong, DK
Cheng, YC
Rowinsky, EK
机构
[1] MAYO CLIN & MAYO FDN,DIV HEMATOL,ROCHESTER,MN 55905
[2] MAYO CLIN & MAYO FDN,MAYO MED SCH,DEPT PHARMACOL,ROCHESTER,MN 55905
[3] JOHNS HOPKINS UNIV,SCH MED,JOHNS HOPKINS ONCOL CTR,ADULT LEUKEMIA PROGRAM,BALTIMORE,MD 21205
[4] JOHNS HOPKINS UNIV,SCH MED,JOHNS HOPKINS ONCOL CTR,DIV MED ONCOL,BALTIMORE,MD 21205
[5] JOHNS HOPKINS UNIV,SCH MED,JOHNS HOPKINS ONCOL CTR,DIV PHARMACOL,BALTIMORE,MD 21205
[6] JOHNS HOPKINS UNIV,SCH MED,JOHNS HOPKINS ONCOL CTR,DIV EXPT THERAPEUT,BALTIMORE,MD 21205
[7] YALE UNIV,SCH MED,DEPT PHARMACOL,NEW HAVEN,CT 06510
关键词
ACUTE MYELOGENOUS LEUKEMIA; CAMPTOTHECIN ACTIVITY; PHASE-I; RESISTANT; VIVO; LINE; PROLIFERATION; SENSITIVITY; INDUCTION; INHIBITOR;
D O I
10.1182/blood.V89.6.2098
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mu mol/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 mu mol/L (median, 30 mu mol/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. (C) 1997 by The American Society of Hematology.
引用
收藏
页码:2098 / 2104
页数:7
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