Candidate genes for cross-resistance against DNA-damaging drugs

Rainer Wittig; Michelle Nessling; Rainer D Will; Jan Mollenhauer; Rüdiger Salowsky; Ewald Münstermann; Matthias Schick; Heike Helmbach; Brigitte Gschwendt; Bernhard Korn; Petra Kioschis; Peter Lichter; Dirk Schadendorf; Annemarie Poustka; H Helmbach

Candidate genes for cross-resistance against DNA-damaging drugs

Rainer Wittig, Michelle Nessling, Rainer D Will, Jan Mollenhauer, Rüdiger Salowsky, Ewald Münstermann, Matthias Schick, Heike Helmbach, Brigitte Gschwendt, Bernhard Korn, Petra Kioschis, Peter Lichter, Dirk Schadendorf, Annemarie Poustka, H Helmbach

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA-damaging agents cisplatin, etoposide, and fotemustine. Subarray analyses confirmed 57 candidate genes recovered from a genome-wide scan for differential expression. By specifically addressing cancer genes we retrieved another set of 209 candidates. Exemplary Northern blot studies indicated qualitative concordance for 110 of 135 (81.4%) data points. Whereas the etoposide-resistant line showed constant expression patterns over a period of approximately 2.5 years, the fotemustine- and cisplatin-resistant sublines exhibited considerable variability. Initially representing distinct entities, these two sublines finally converged in their expression patterns. A total of 110 genes was transiently or permanently deregulated in at least two resistant sublines. Fourteen genes displayed differential expression in all three of the sublines. We hypothesize that the variations in fotemustine and cisplatin resistance are based on progressive optimization and/or polyclonality. This, in addition to genomic alterations investigated by comparative genomic hybridization and evaluation of short-term response genes, can be used as a criterion for the selection of promising candidates. Among these are CYR61, AHCYL1, and MPP1, as well as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs.

Original language	English
Pages (from-to)	6698-705
Number of pages	8
Journal	Cancer Research
Volume	62
Issue number	22
Publication status	Published - 15 Nov 2002

Keywords

Antineoplastic Agents
Apoptosis
Blotting, Northern
Cisplatin
Cluster Analysis
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Etoposide
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Melanoma
Nitrosourea Compounds
Nucleic Acid Hybridization
Organophosphorus Compounds
Tumor Cells, Cultured

Cite this

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title = "Candidate genes for cross-resistance against DNA-damaging drugs",

abstract = "Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA-damaging agents cisplatin, etoposide, and fotemustine. Subarray analyses confirmed 57 candidate genes recovered from a genome-wide scan for differential expression. By specifically addressing cancer genes we retrieved another set of 209 candidates. Exemplary Northern blot studies indicated qualitative concordance for 110 of 135 (81.4\%) data points. Whereas the etoposide-resistant line showed constant expression patterns over a period of approximately 2.5 years, the fotemustine- and cisplatin-resistant sublines exhibited considerable variability. Initially representing distinct entities, these two sublines finally converged in their expression patterns. A total of 110 genes was transiently or permanently deregulated in at least two resistant sublines. Fourteen genes displayed differential expression in all three of the sublines. We hypothesize that the variations in fotemustine and cisplatin resistance are based on progressive optimization and/or polyclonality. This, in addition to genomic alterations investigated by comparative genomic hybridization and evaluation of short-term response genes, can be used as a criterion for the selection of promising candidates. Among these are CYR61, AHCYL1, and MPP1, as well as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs.",

keywords = "Antineoplastic Agents, Apoptosis, Blotting, Northern, Cisplatin, Cluster Analysis, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Etoposide, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Melanoma, Nitrosourea Compounds, Nucleic Acid Hybridization, Organophosphorus Compounds, Tumor Cells, Cultured",

author = "Rainer Wittig and Michelle Nessling and Will, \{Rainer D\} and Jan Mollenhauer and R{\"u}diger Salowsky and Ewald M{\"u}nstermann and Matthias Schick and Heike Helmbach and Brigitte Gschwendt and Bernhard Korn and Petra Kioschis and Peter Lichter and Dirk Schadendorf and Annemarie Poustka and H Helmbach",

year = "2002",

month = nov,

day = "15",

language = "English",

volume = "62",

pages = "6698--705",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "22",

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TY - JOUR

T1 - Candidate genes for cross-resistance against DNA-damaging drugs

AU - Wittig, Rainer

AU - Nessling, Michelle

AU - Will, Rainer D

AU - Mollenhauer, Jan

AU - Salowsky, Rüdiger

AU - Münstermann, Ewald

AU - Schick, Matthias

AU - Helmbach, Heike

AU - Gschwendt, Brigitte

AU - Korn, Bernhard

AU - Kioschis, Petra

AU - Lichter, Peter

AU - Schadendorf, Dirk

AU - Poustka, Annemarie

AU - Helmbach, H

PY - 2002/11/15

Y1 - 2002/11/15

N2 - Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA-damaging agents cisplatin, etoposide, and fotemustine. Subarray analyses confirmed 57 candidate genes recovered from a genome-wide scan for differential expression. By specifically addressing cancer genes we retrieved another set of 209 candidates. Exemplary Northern blot studies indicated qualitative concordance for 110 of 135 (81.4%) data points. Whereas the etoposide-resistant line showed constant expression patterns over a period of approximately 2.5 years, the fotemustine- and cisplatin-resistant sublines exhibited considerable variability. Initially representing distinct entities, these two sublines finally converged in their expression patterns. A total of 110 genes was transiently or permanently deregulated in at least two resistant sublines. Fourteen genes displayed differential expression in all three of the sublines. We hypothesize that the variations in fotemustine and cisplatin resistance are based on progressive optimization and/or polyclonality. This, in addition to genomic alterations investigated by comparative genomic hybridization and evaluation of short-term response genes, can be used as a criterion for the selection of promising candidates. Among these are CYR61, AHCYL1, and MPP1, as well as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs.

AB - Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA-damaging agents cisplatin, etoposide, and fotemustine. Subarray analyses confirmed 57 candidate genes recovered from a genome-wide scan for differential expression. By specifically addressing cancer genes we retrieved another set of 209 candidates. Exemplary Northern blot studies indicated qualitative concordance for 110 of 135 (81.4%) data points. Whereas the etoposide-resistant line showed constant expression patterns over a period of approximately 2.5 years, the fotemustine- and cisplatin-resistant sublines exhibited considerable variability. Initially representing distinct entities, these two sublines finally converged in their expression patterns. A total of 110 genes was transiently or permanently deregulated in at least two resistant sublines. Fourteen genes displayed differential expression in all three of the sublines. We hypothesize that the variations in fotemustine and cisplatin resistance are based on progressive optimization and/or polyclonality. This, in addition to genomic alterations investigated by comparative genomic hybridization and evaluation of short-term response genes, can be used as a criterion for the selection of promising candidates. Among these are CYR61, AHCYL1, and MPP1, as well as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs.

KW - Antineoplastic Agents

KW - Apoptosis

KW - Blotting, Northern

KW - Cisplatin

KW - Cluster Analysis

KW - Drug Resistance, Multiple

KW - Drug Resistance, Neoplasm

KW - Etoposide

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Melanoma

KW - Nitrosourea Compounds

KW - Nucleic Acid Hybridization

KW - Organophosphorus Compounds

KW - Tumor Cells, Cultured

M3 - Article

C2 - 12438269

SN - 0008-5472

VL - 62

SP - 6698

EP - 6705

JO - Cancer Research

JF - Cancer Research

IS - 22

ER -

Candidate genes for cross-resistance against DNA-damaging drugs

Abstract

Keywords

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