In vitro topo II--DNA complex accumulation and cytotoxicity of etoposide in leukaemic cells from patients with acute myelogenous and chronic lymphocytic leukaemia.
Topoisomerase II (topo II) is the target enzyme of etoposide, and DNA--topo II complex accumulation is considered crucial for the cytotoxic effect. We used a SDS--KCl precipitation assay to determine the complex accumulation induced by etoposide in leukaemic cells isolated from 58 patients, 31 with acute myelogenous leukaemia (AML), and 27 with chronic lymphocytic leukaemia (CLL). To investigate whether the sensitivity towards etoposide was dependent on the complex accumulation in the cells, we investigated the drug-induced DNA damage using a DNA unwinding assay and the in vitro cytotoxicity of etoposide using the MTT assay. AML cells had higher complex accumulation (P=0.006) and more DNA damage (P=0.029) compared with CLL cells. The data support a relationship between etoposide-induced complex accumulation and DNA damage in leukaemic cells from AML and CLL patients. However, the induced DNA damage did not translate to in vitro cytotoxicity, suggesting that other factors, such as DNA repair and apoptosis functions, also play important roles to determine the etoposide sensitivity.
Wang
Y
Y
Department of Oncology-Pathology at Radiumhemmet, CCK, R8-00, Karolinska Institute and Hospital, S-171 76 Stockholm, Sweden. yuying.wang@cck.ki.se
Zhou
R
R
Liliemark
J
J
Gruber
A
A
Lindemalm
S
S
Albertioni
F
F
Liliemark
E
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D005047:Etoposide / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged
D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D005047:Etoposide; D004250:DNA Topoisomerases, Type II