This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hinds, M. Articles by Zwelling, L. A. Search for Related Content PubMed PubMed Citation Articles by Hinds, M. Articles by Zwelling, L. A.

Identification of a Point Mutation in the Topoisomerase II Gene from a Human Leukemia Cell Line Containing an Amsacrine-resistant Form of Topoisomerase II¹

Department of Medical Oncology, Division of Medicine, The University of Texas M. D. Anderson Cancer Center [M. H., K. D., J. M., E. A., L. A. Z.]; and Howard Hughes Medical Institute and Departments of Cell Biology and Pediatrics, Baylor College of Medicine [R. J., F. D. L.], Houston, Texas 77030

HL-60/AMSA is a human leukemia cell line that is 50- to 100-fold more resistant to the cytotoxic actions of the topoisomerase II-reactive intercalator amsacrine than is its drug-sensitive HL-60 parent line. Previously, we have shown that the topoisomerase II from HL-60/AMSA is also resistant to inhibition by amsacrine and other intercalating agents. We therefore sought the molecular basis for the resistance of the topoisomerase II of HL-60/AMSA and, by inference, of the HL-60/AMSA line itself. We report the cloning and sequencing of the topoisomerase II genes from both the sensitive and resistant leukemia cell lines using polymerase chain reaction technology. We have identified a single base change associated with the drug-resistant form of topoisomerase II. This mutation is present in both cloned HL-60/AMSA complementary DNA and extracted HL-60/AMSA genomic DNA. A rapid assay for this mutation in clinical samples has been developed and applied to the DNA of cells from both normal volunteers and leukemia patients. Thus far, the HL-60/AMSA genotype has not been identified in the cells from any individual, suggesting that this genotype is indeed a mutation and not an allelic form of topoisomerase II. The novel assay developed will allow a rapid search for the prevalence of this mutation in clinical samples from patients with leukemia who have relapsed following intercalator therapy.

¹ This study was supported by USPHS Grant CA40090 (L. A. Z.) and Grant CH-324D from the American Cancer Society (L. A. Z.).

² To whom requests for reprints should be addressed, at Box 52, 1515 Holcombe Blvd., Houston, TX 77030.

Received 6/25/91. Accepted 7/16/91.

This article has been cited by other articles:

				C. Leontiou, G. P. Watters, K. L. Gilroy, P. Heslop, I. G. Cowell, K. Craig, R. N. Lightowlers, J. H. Lakey, and C. A. Austin Differential Selection of Acridine Resistance Mutations in Human DNA Topoisomerase IIbeta Is Dependent on the Acridine Structure Mol. Pharmacol., April 1, 2007; 71(4): 1006 - 1014. [Abstract] [Full Text] [PDF]

				C. Leontiou, J. H. Lakey, R. Lightowlers, R. M. Turnbull, and C. A. Austin Mutation P732L in Human DNA Topoisomerase IIbeta Abolishes DNA Cleavage in the Presence of Calcium and Confers Drug Resistance Mol. Pharmacol., January 1, 2006; 69(1): 130 - 139. [Abstract] [Full Text] [PDF]

				C. Leontiou, J. H. Lakey, and C. A. Austin Mutation E522K in Human DNA Topoisomerase II{beta} Confers Resistance to Methyl N-(4'-(9-acridinylamino)-phenyl)carbamate hydrochloride and Methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide but Hypersensitivity to Etoposide Mol. Pharmacol., September 1, 2004; 66(3): 430 - 439. [Abstract] [Full Text] [PDF]

				N. Vilain, M. Tsai-Pflugfelder, A. Benoit, S. M. Gasser, and D. Leroy Modulation of drug sensitivity in yeast cells by the ATP-binding domain of human DNA topoisomerase II{alpha} Nucleic Acids Res., October 1, 2003; 31(19): 5714 - 5722. [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]

				S. Patel, B. A. Keller, and L. M. Fisher Mutations at Arg486 and Glu571 in Human Topoisomerase IIalpha Confer Resistance to Amsacrine: Relevance for Antitumor Drug Resistance in Human Cells Mol. Pharmacol., April 1, 2000; 57(4): 784 - 791. [Abstract] [Full Text]

				Z. Zhou, L. A. Zwelling, Y. Kawakami, T. An, K. Kobayashi, C. Herzog, and E. S. Kleinerman Adenovirus-mediated Human Topoisomerase II{{alpha}} Gene Transfer Increases the Sensitivity of Etoposide-resistant Human Breast Cancer Cells Cancer Res., September 1, 1999; 59(18): 4618 - 4624. [Abstract] [Full Text] [PDF]

				S. H. Elsea, Y. Hsiung, J. L. Nitiss, and N. Osheroff A Yeast Type II Topoisomerase Selected for Resistance to Quinolones J. Biol. Chem., January 27, 1995; 270(4): 1913 - 1920. [Abstract] [Full Text] [PDF]