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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

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⁴ V. Moneo and A. Carnero et al., unpublished data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