Multidrug resistance due to impaired DNA cleavage in a VP-16-resistant human leukemia cell line.
We established a VP-16-resistant line of human leukemia cells, K562/VP-H2, derived from K562 cells. K562/VP-H2 cells were 44-fold more resistant to VP-16 than were K562 cells. K562/VP-H2 cells were also resistant to doxorubicin, daunorubicin and mitoxantrone, but showed little or no resistance to vincristine, aclarubicin, idarubicin, idarubicinol, cytosine arabinoside, cis-platinum or camptothecin. K562/VP-H2 cells did not over-express P-glycoprotein or multidrug resistance protein, and showed intracellular accumulation of VP-16 similar to that in K562 cells. While the expressions of topoisomerase II-alpha gene and topoisomerase II-beta gene, or catalytic activity in nuclear extract of K562/VP-H2 cells were similar to that of K562 cells, the VP-16 induced DNA cleavage was reduced in K562/VP-H2 cells compared to K562 cells, suggesting that the reduction of topoisomerase II-mediated DNA cleavage through qualitative alteration of topoisomerase II may be the main mechanism of acquired multidrug resistance for K562/VP-H2 cells. The K562/VP-H2 cell line is an interesting model for studying resistance to antileukemia drugs targeting topoisomerase II.
Fukushima
T
T
First Department of Internal Medicine, Fukui Medical University, Japan. tfukus@fmsrsa.fukui-med.ac.jp
Takemura
H
H
Yamashita
T
T
Ishisaka
T
T
Inai
K
K
Imamura
S
S
Urasaki
Y
Y
Ueda
T
T
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002384:Catalysis; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D005047:Etoposide; D004250:DNA Topoisomerases, Type II