Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance

Kohichiroh Yasui, Saori Mihara, Chen Zhao, Hiroyuki Okamoto, Fumiko Saito-Ohara, Akihiro Tomida, Tadao Funato, Akira Yokomizo, Seiji Naito, Issei Imoto, Takashi Tsuruo, Johji Inazawa

Research output: Contribution to journalArticle

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Abstract

Chemoresistance is a major obstacle for successful treatment of cancer. To identify regions of the genome associated with acquired resistance to therapeutic drugs, we conducted molecular cytogenetic analyses of 23 cancer-cell lines, each resistant to either camptothecin, cisplatin, etoposide (VP-16), Adriamycin, or 1-β-D-arabinofuranosylcytosine, although the parental tumor lines were not. Subtractive comparative genomic hybridization studies revealed regions of gain or loss in DNA-copy numbers that were characteristic of drug-resistant cell lines; i.e., differences from their drug-sensitive parental cell lines. Thirteen ATP-binding cassette (ABC) transporter genes [ABCA3, ABCB1 (MDR1), ABCB6, ABCB8, ABCB10, ABCB11, ABCC1 (MRP1), ABCC4, ABCC9, ABCD3, ABCD4, ABCE1, and ABCF2] were amplified among 19 of the resistant cell lines examined. Three genes encoding antiapoptotic BCL-2 proteins (BCL2L2, MCL1, and BCL2L10) were also amplified and consequently overexpressed in three of the derivative lines. Down-regulation of BCL2L2 with an antisense oligonucleotide sensitized a VP-16 resistant ovarian-cancer cell line (SKOV3/ VP) to VP-16. A decrease in copy numbers of genes encoding deoxycytidine kinase, DNA topoisomerase I, and DNA topoisomerase II α reduced their expression levels in one cytosine arabinoside-resistant line, two of three camptothecin-resistant lines, and two of five VP-16-resistant cell lines, respectively. Our results indicated that changes in DNA-copy numbers of the genes mentioned can activate or down-regulate them in drug-resistant cell lines, and that such genomic alterations might be implicated in acquired chemoresistance.

Original languageEnglish
Pages (from-to)1403-1410
Number of pages8
JournalCancer Research
Volume64
Issue number4
DOIs
Publication statusPublished - Feb 15 2004

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Gene Dosage
Drug Resistance
Etoposide
Cell Line
Camptothecin
Cytarabine
Pharmaceutical Preparations
Down-Regulation
Deoxycytidine Kinase
DNA Copy Number Variations
Genes
Viral Structural Proteins
Neoplasms
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Comparative Genomic Hybridization
ATP-Binding Cassette Transporters
Antisense Oligonucleotides
Cytogenetic Analysis
Ovarian Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yasui, K., Mihara, S., Zhao, C., Okamoto, H., Saito-Ohara, F., Tomida, A., ... Inazawa, J. (2004). Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance. Cancer Research, 64(4), 1403-1410. https://doi.org/10.1158/0008-5472.CAN-3263-2

Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance. / Yasui, Kohichiroh; Mihara, Saori; Zhao, Chen; Okamoto, Hiroyuki; Saito-Ohara, Fumiko; Tomida, Akihiro; Funato, Tadao; Yokomizo, Akira; Naito, Seiji; Imoto, Issei; Tsuruo, Takashi; Inazawa, Johji.

In: Cancer Research, Vol. 64, No. 4, 15.02.2004, p. 1403-1410.

Research output: Contribution to journalArticle

Yasui, K, Mihara, S, Zhao, C, Okamoto, H, Saito-Ohara, F, Tomida, A, Funato, T, Yokomizo, A, Naito, S, Imoto, I, Tsuruo, T & Inazawa, J 2004, 'Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance', Cancer Research, vol. 64, no. 4, pp. 1403-1410. https://doi.org/10.1158/0008-5472.CAN-3263-2
Yasui K, Mihara S, Zhao C, Okamoto H, Saito-Ohara F, Tomida A et al. Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance. Cancer Research. 2004 Feb 15;64(4):1403-1410. https://doi.org/10.1158/0008-5472.CAN-3263-2
Yasui, Kohichiroh ; Mihara, Saori ; Zhao, Chen ; Okamoto, Hiroyuki ; Saito-Ohara, Fumiko ; Tomida, Akihiro ; Funato, Tadao ; Yokomizo, Akira ; Naito, Seiji ; Imoto, Issei ; Tsuruo, Takashi ; Inazawa, Johji. / Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance. In: Cancer Research. 2004 ; Vol. 64, No. 4. pp. 1403-1410.
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