Summary
Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitrosourea) is the most commonly used chemotherapeutic agent for gliomas. However, the usefulness of this agent is limited because tumor cell resistance to BCNU is frequently found in clinical brain tumor therapy. The O 6 -methylguanine-DNA methyltransferase protein (MGMT) reverses alkylation at the O 6 position of guanine and we have reported the role of MGMT in the response of brain tumors to alkylating agents. However, the different mechanisms underlying the patterns related to MGMT remain unclear. To better understand the molecular mechanism by which BCNU exerts its effect in glioma cell lines according MGMT expression, we used microarray technology to interrogate 3800 known genes and determine the gene expression profiles altered by BCNU treatment. Our results showed that treatment with BCNU alters the expression of a diverse group of genes in a time-dependent manner. A subset of gene changes was found common in both glioma cell lines and other subset is specific of each cell line. After 24 h of BCNU treatment, up-regulation of transcription factors involved in the nucleation of both RNA polymerase II and III transcription initiation complexes was reported. Interestingly, BCNU promoted the expression of actin-dependent regulators of chromatin. Similar effects were found with higher BCNU doses in MGMT+ cell line showing a similar mechanism that in MGMT-deficient cell with standard doses. Our data suggest that human glioma cell lines treated with BCNU, independently of MGMT expression, show changes in the expression of cell cycle and survival-related genes interfering the transcription mechanisms and the chromatin regulation.
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MD Walker SB Green DP Byar E Alexander SuffixJr U Batzdorf WH Brooks WE Hunt CS MacCarty MS Mahaley SuffixJr J Mealey SuffixJr G Owens J Ransohoff SuffixII JT Robertson WR Shapiro KR Smith SuffixJr CB Wilson TA Strike (1980) ArticleTitleRandomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery N Engl J Med 30 1323–1329
CH Chang J Horton D Schoenfeld O Salazer R Perez Tamayo S Kramer A Weinstein SJ Nelson Y Tsukada (1983) ArticleTitleComparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group Study Cancer 52 997–1007
CL Nutt M Noble AF Chambers JG Cairncross (2000) ArticleTitleDifferential expression of drug resistance genes and chemosensitivity in glial cell lineages correlate with differential response of oligodendrogliomas and astrocytomas to chemotherapy Cancer Res 60 4812–4818 Occurrence Handle1:CAS:528:DC%2BD3cXmsFWhs7s%3D Occurrence Handle10987291
ME Dolan CD Corsico AE Pegg (1985) ArticleTitleExposure of HeLa cells to 0(6)-alkylguanines increases sensitivity to the cytotoxic effects of alkylating agents Biochem Biophys Res Commun 132 178–185 Occurrence Handle10.1016/0006-291X(85)91004-6 Occurrence Handle1:CAS:528:DyaL28XhtVCjtr8%3D Occurrence Handle4062928
AE Pegg (1990) ArticleTitleMammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents Cancer Res 50 6119–6129
M Belanich M Pastor T Randall D Guerra J Kibitel L Alas B Li M Citron P Wasserman A White H Eyre K Jaeckle S Schulman D Rector M Prados S Coons W Shapiro D Yarosh (1996) ArticleTitleRetrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine Cancer Res 56 783–788 Occurrence Handle1:CAS:528:DyaK28XhtVClsLc%3D Occurrence Handle8631014
KA Jaeckle HJ Eyre JJ Townsend S Schulman HM Knudson M Belanich DB Yarosh SI Bearman DJ Giroux SC Schold (1998) ArticleTitleCorrelation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study J Clin Oncol 16 3310–3315 Occurrence Handle1:CAS:528:DyaK1cXmvFGrtbw%3D Occurrence Handle9779706
JR Silber A Blank MS Bobola S Ghatan DD Kolstoe MS Berger (1999) ArticleTitleO6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy Clin Cancer Res 5 807–814 Occurrence Handle1:CAS:528:DyaK1MXislOnsLY%3D Occurrence Handle10213216
M Esteller J Garcia-Foncillas E Andion SN Goodman OF Hidalgo V Vanaclocha SB Baylin JG Herman (2000) ArticleTitleInactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents N Engl J Med 343 1350–1354 Occurrence Handle10.1056/NEJM200011093431901 Occurrence Handle1:CAS:528:DC%2BD3cXosFOltLg%3D Occurrence Handle11070098
M Schena D Shalon R Heller A Chai PO Brown RW Davis (1996) ArticleTitleParallel human genome analysis: microarray-based expression monitoring of 1000 genes Proc Natl Acad Sci USA 93 10614–10619 Occurrence Handle10.1073/pnas.93.20.10614 Occurrence Handle1:CAS:528:DyaK28XmtVOlsbo%3D Occurrence Handle8855227
J DeRisi L Penland PO Brown ML Bittner PS Meltzer M Ray Y Chen YA Su JM Trent (1996) ArticleTitleUse of a cDNA microarray to analyse gene expression patterns in human cancer Nat Genet 14 457–460 Occurrence Handle10.1038/ng1296-457 Occurrence Handle1:CAS:528:DyaK28XntlGgtLo%3D Occurrence Handle8944026
RA Heller M Schena A Chai D Shalon T Bedilion J Gilmore DE Woolley RW Davis (1997) ArticleTitleDiscovery and analysis of inflammatory disease-related genes using cDNA microarrays Proc Natl Acad Sci USA 94 2150–2155 Occurrence Handle10.1073/pnas.94.6.2150 Occurrence Handle1:CAS:528:DyaK2sXhvF2lt70%3D Occurrence Handle9122163
DJ Lockhart H Dong MC Byrne MT Follettie MV Gallo MS Chee M Mittmann C Wang M Kobayashi H Horton EL Brown (1996) ArticleTitleExpression monitoring by hybridization to high-density oligonucleotide arrays Nat Biotechnol 14 1675–1680 Occurrence Handle10.1038/nbt1296-1675 Occurrence Handle1:CAS:528:DyaK28XnsV2ktLo%3D Occurrence Handle9634850
M Weller J Rieger C Grimmel EG Van Meir N De Tribolet S Krajewski JC Reed A Deimling Particlevon J Dichgans (1998) ArticleTitlePredicting chemoresistance in human malignant glioma cells: the role of molecular genetic analyses Int J Cancer 79 640–644 Occurrence Handle10.1002/(SICI)1097-0215(19981218)79:6<640::AID-IJC15>3.0.CO;2-Z Occurrence Handle1:CAS:528:DyaK1MXltlc%3D Occurrence Handle9842975
A Gomi S Shinoda R Sakai H Hirai K Ozawa T Masuzawa (1996) ArticleTitleElevated expression of DNA polymerase beta gene in glioma cell lines with acquired resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea Biochem Biophys Res Commun 227 558–563 Occurrence Handle10.1006/bbrc.1996.1545 Occurrence Handle1:CAS:528:DyaK28Xmt1Kgu7s%3D Occurrence Handle8878552
B Ma N Hernandez (2001) ArticleTitleA map of protein–protein contacts within the small nuclear RNA-activating protein complex SNAPc J Biol Chem 276 5027–5035 Occurrence Handle10.1074/jbc.M009301200 Occurrence Handle1:CAS:528:DC%2BD3MXhtlOqu74%3D Occurrence Handle11056176
H Han DJ Bearss LW Browne R Calaluce RB Nagle DD Von Hoff (2002) ArticleTitleIdentification of differentially expressed genes in pancreatic cancer cells using cDNA microarray Cancer Res 62 2890–2896 Occurrence Handle1:CAS:528:DC%2BD38XjvFSmt7c%3D Occurrence Handle12019169
I Takemasa H Higuchi H Yamamoto M Sekimoto N Tomita S Nakamori R Matoba M Monden K Matsubara (2001) ArticleTitleConstruction of preferential cDNA microarray specialized for human colorectal carcinoma: molecular sketch of colorectal cancer Biochem Biophys Res Commun, 285 1244–1249
J Xu JA Stolk X Zhang SJ Silva RL Houghton M Matsumura TS Vedvick KB Leslie R Badaro SG Reed (2002) ArticleTitleIdentification of differentially expressed genes in human prostate cancer using subtraction and microarray Cancer Res 60 1677–1682
K Kudoh M Ramanna R Ravatn AG Elkahloun ML Bittner PS Meltzer JM Trent WS Dalton KV Chin (2000) ArticleTitleMonitoring the expression profiles of doxorubicin-induced and doxorubicin-resistant cancer cells by cDNA microarray Cancer Res 60 4161–4166 Occurrence Handle1:CAS:528:DC%2BD3cXlvFOkt7g%3D Occurrence Handle10945624
H Zembutsu Y Ohnishi T Tsunoda Y Furukawa T Katagiri Y Ueyama N Tamaoki T Nomura O Kitahara R Yanagawa K Hirata Y Nakamura (2002) ArticleTitleGenome-wide cDNA microarray screening to correlate gene expression profiles with sensitivity of 85 human cancer xenografts to anticancer drugs Cancer Res 62 518–527 Occurrence Handle1:CAS:528:DC%2BD38XhtVyht7c%3D Occurrence Handle11809704
J Okutsu T Tsunoda Y Kaneta T Katagiri O Kitahara H Zembutsu R Yanagawa S Miyawaki K Kuriyama N Kubota Y Kimura K Kubo F Yagasaki T Higa H Taguchi T Tobita H Akiyama A Takeshita YH Wang T Motoji R Ohno Y Nakamura (2002) ArticleTitlePrediction of chemosensitivity for patients with acute myeloid leukemia, according to expression levels of 28 genes selected by genome-wide complementary DNA microarray analysis Mol Cancer Ther 1 1035–1042 Occurrence Handle1:CAS:528:DC%2BD3sXmtFantg%3D%3D Occurrence Handle12481426
BA Teicher (1997) Antitumor alkylating agents VT De Vita SuffixJr S Hellman SA Rosenberg (Eds) Cancer: Principles and Practice of Oncology EditionNumber5 Lippincott-Raven Philadelphia 405–418
M Colvin J Hilton (1981) ArticleTitlePharmacology of cyclophosphamide and metabolites Cancer Treat 65 (Suppl 3) 65 89–95 Occurrence Handle1:CAS:528:DyaL38XlslCht78%3D
DB Ludlum (1990) ArticleTitleDNA alkylation by the haloethylnitrosoureas: nature of modifications produced and their enzymatic repair or removal Mutat Res 233 117–126 Occurrence Handle1:CAS:528:DyaK3MXhvFSjtw%3D%3D Occurrence Handle2233793
AE Pegg ME Dolan RC Moschel (1995) ArticleTitleStructure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase Prog Nucleic Acid Res Mol Biol 51 167–223 Occurrence Handle1:CAS:528:DyaK2MXos1ertL0%3D Occurrence Handle7659775
M Purrello C Di Pietro A Rapisarda V Amico V Giunta H Engel S Stevens Y Hsieh M Teichman Z Wang G Sichel R Roeder KH Grzeschik (2001) ArticleTitleGenes for human general transcription initiation factors TFIIIB, TFIIIB-associated proteins, TFIIIC2 and PTF/SNAPC: functional and positional candidates for tumour predisposition or inherited genetic diseases? Oncogene 20 4877–4883 Occurrence Handle10.1038/sj.onc.1204604 Occurrence Handle1:CAS:528:DC%2BD3MXmtlCrsbw%3D Occurrence Handle11521199
HZ Ring V Vameghi-Meyers W Wang GR Crabtree U Francke (1998) ArticleTitleFive SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) genes are dispersed in the human genome Genomics 51 140–143 Occurrence Handle10.1006/geno.1998.5343 Occurrence Handle1:CAS:528:DyaK1cXltFentbo%3D Occurrence Handle9693044
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Bandres, E., Andion, E., Escalada, A. et al. Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol 73, 189–198 (2005). https://doi.org/10.1007/s11060-004-5174-5
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DOI: https://doi.org/10.1007/s11060-004-5174-5