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Research Articles: Therapeutics

Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line

¹ INSERM U612 and ² INSERM U509, Research Section, Institut Curie, Paris, France; ³ Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France; ⁴ INSERM U711, Hôpital de la Salpêtrière, Paris, France; and ⁵ UMR 5202, Biodiversity, Origin, Structure, and Evolution, Museum d'Histoire Naturelle, Paris, France

Requests for reprints: Marie-France Poupon, INSERM U612, Research Section, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France. Phone: 33-1-4234-6629. Fax: 33-1-4234-6619. E-mail: mfpoupon{at}curie.fr

Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O⁶-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O⁶-methylguanine-DNA methyltransferase or are mismatch repair–deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor. [Mol Cancer Ther 2006;5(9):2182–92]

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⁶ http://www.bionet.espci.fr/varan/varan_info.htm.

⁷ http://frodo.wi.mit.edu/cgi-bin/primer3/primer3, www.cgi.

Received 10/17/05; revised 5/30/06; accepted 6/29/06.