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Molecular Pharmacology

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Research ArticleArticle

Induction of Alkylator (Melphalan) Resistance in HL60 Cells Is Accompanied by Increased Levels of Topoisomerase II Expression and Function

Q. Q. Pu and W. R. Bezwoda
Molecular Pharmacology July 1999, 56 (1) 147-153; DOI: https://doi.org/10.1124/mol.56.1.147
Q. Q. Pu
Division of Clinical Hematology and Medical Oncology, Department of Medicine, University of the Witwatersrand Medical School, Parktown, South Africa
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W. R. Bezwoda
Division of Clinical Hematology and Medical Oncology, Department of Medicine, University of the Witwatersrand Medical School, Parktown, South Africa
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Abstract

Human leukemic HL60 cells were selected for resistance to alkylating agents by stepwise exposure to increasing concentrations ofl-phenylalanine mustard (melphalan). The resulting resistant cell line (R-HL60) was 4-fold resistant (melphalan IC50 value, 27.84 ± 4.2 μM) to melphalan compared with parental HL60 cells (melphalan IC50 value, 6.9 ± 1.78 μM). Nuclear extracts from R-HL60 cells possess a ∼4-fold increase in DNA topoisomerase II activity compared with parental HL60 cells. As determined using Western blot analysis, the level of topoisomerase IIα protein expressed inR-HL60 cells was approximately 3-fold that of parental HL60 cells. However, there were no differences observed in the level of topoisomerase IIβ protein, in the topoisomerase I activity, or in the level of topoisomerase I protein expression comparing the two cell lines. R-HL60 cells were 5-fold more sensitive than parental HL60 cells to the cytotoxic effect of the topoisomerase II inhibitor doxorubicin. The sensitivity to the cytotoxic effects of the topoisomerase I inhibitor camptothecin did not differ inR-HL60 and parental HL60 cell lines. Preincubation with doxorubicin significantly increased melphalan-induced interstrand DNA cross-link formation and cytotoxicity in R-HL60 cells compared with the parental HL60 cells. The affinity of topoisomerase II for UV-irradiated cross-linked HL60 DNA was increased by ∼2.5-fold compared with that of HL60 native DNA. The affinity of topoisomerase II for both UV-irradiated (cross-linked) and native DNA was significantly decreased after doxorubicin pretreatment. Elevated topoisomerase II activity and the increased affinity of topoisomerase II for cross-linked DNA in melphalan-resistant cells seems to contribute to alkylator resistance by changing DNA topology, thereby facilitating DNA repair.

Footnotes

    • Received June 29, 1998.
    • Accepted March 24, 1999.
  • Send reprint requests to: Dr. W. R. Bezwoda, Division of Clinical Hematology and Medical Oncology, University of the Witwatersrand Medical School, Department of Medicine, 7 York Rd., Parktown, 2193, South Africa. E-mail:014pu{at}chiron.wits.ac.za

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Molecular Pharmacology: 56 (1)
Molecular Pharmacology
Vol. 56, Issue 1
1 Jul 1999
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Research ArticleArticle

Induction of Alkylator (Melphalan) Resistance in HL60 Cells Is Accompanied by Increased Levels of Topoisomerase II Expression and Function

Q. Q. Pu and W. R. Bezwoda
Molecular Pharmacology July 1, 1999, 56 (1) 147-153; DOI: https://doi.org/10.1124/mol.56.1.147

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Research ArticleArticle

Induction of Alkylator (Melphalan) Resistance in HL60 Cells Is Accompanied by Increased Levels of Topoisomerase II Expression and Function

Q. Q. Pu and W. R. Bezwoda
Molecular Pharmacology July 1, 1999, 56 (1) 147-153; DOI: https://doi.org/10.1124/mol.56.1.147
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