This Article Full Text 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 Martínez, N. Articles by Piris, M. A. Search for Related Content PubMed PubMed Citation Articles by Martínez, N. Articles by Piris, M. A.

¹ Molecular Pathology Programme and ² Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas and ³ Pharmamar R&D, Madrid, Spain

Requests for reprints: Miguel Angel Piris, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, C/ Melchor Fernández Almagro 3, E-28029 Madrid, Spain. Phone: 34-91-224-69-00; Fax: 34-91-224-69-23. E-mail: mapiris{at}cnio.es

Ecteinascidin 743 (ET-743; Yondelis, Trabectedin) is a marine anticancer agent that induces long-lasting objective remissions and tumor control in a subset of patients with pretreated/resistant soft-tissue sarcoma. Drug-induced tumor control is achievable in 22% of such patients, but there is no clear indication of the molecular features correlated with clinical sensitivity/resistance to ET-743. Nine low-passage, soft-tissue sarcoma cell lines, explanted from chemo-naïve patients with different patterns of sensitivity, have been profiled with a cDNA microarray containing 6,700 cancer-related genes. The molecular signature of these cell lines was analyzed at baseline and at four different times after ET-743 exposure. The association of levels of TP53 mutation and TP73 expression with ET-743 sensitivity and cell cycle kinetics after treatment was also analyzed. Gene expression profile analysis revealed up-regulation of 86 genes and down-regulation of 244 genes in response to ET-743. The ET-743 gene expression signature identified a group of genes related with cell cycle control, stress, and DNA-damage response (JUNB, ATF3, CS-1, SAT, GADD45B, and ID2) that were up-regulated in all the cell lines studied. The transcriptional signature 72 hours after ET-743 administration, associated with ET-743 sensitivity, showed a more efficient induction of genes involved in DNA-damage response and apoptosis, such as RAD17, BRCA1, PAR4, CDKN1A, and P53DINP1, in the sensitive cell line group. The transcriptional signature described here may lead to the identification of ET-743 downstream mediators and transcription regulators and the proposal of strategies by which ET-743–sensitive tumors may be identified.

Key Words: Sarcoma • ET-743 • expression profile • time course

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ V. Moneo and A. Carnero et al., unpublished data

⁵ http://bioinfo.cnio.es/genecards/index.html

⁶ http://fatigo.bioinfo.cnio.es/

⁷ http://gepas.bioinfo.cnio.es/cgi-bin/sotarray

⁸ http://redlinfomas.cnio.es/publications/ET743

Received 11/29/04; revised 2/22/05; accepted 3/ 9/05.

This article has been cited by other articles:

				J. Gommeaux, C. Cano, S. Garcia, M. Gironella, S. Pietri, M. Culcasi, M.-J. Pebusque, B. Malissen, N. Dusetti, J. Iovanna, et al. Colitis and Colitis-Associated Cancer Are Exacerbated in Mice Deficient for Tumor Protein 53-Induced Nuclear Protein 1 Mol. Cell. Biol., March 15, 2007; 27(6): 2215 - 2228. [Abstract] [Full Text] [PDF]

				J. Fayette, I. R. Coquard, L. Alberti, D. Ranchere, H. Boyle, and J.-Y. Blay ET-743: A Novel Agent with Activity in Soft Tissue Sarcomas Oncologist, November 1, 2005; 10(10): 827 - 832. [Abstract] [Full Text] [PDF]