Trabectedin mechanism of action: what's new?

被引:39
作者
D'Incalci, Maurizio [1 ]
机构
[1] IRCCS Ist Ric Farmacol Mario Negri, Dept Oncol, Milan, Italy
关键词
antitumor activity; mechanism of action; trabectedin; tumor microenvironment; ANTITUMOR;
D O I
10.2217/fon.13.207
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Trabectedin is a tetrahydroisoquinoline molecule that binds to the N2 of guanine in the minor groove, causing DNA damage and affecting transcription regulation in a promoter- and gene-specific manner. The antitumor activity of trabectedin appears to be not only related to its direct effects on cancer cells, but also on the tumor microenvironment. In cancer cells, the drug induces cell cycle arrest and cell death that is not dependent on p53 status, and it is increased dramatically in cells deficient in homologous recombination (e.g., cells with mutations of BRCA1/2). Trabectedin also has potent immunomodulatory effects, being selectively cytotoxic against monocytes and tumor-associated macrophages. In addition, it inhibits production of proinflammatory and angiogenic mediators, which induces changes in the tumor microenvironment and contributes to its antitumor activity. The opportunity to combine direct cytotoxic activity with a capacity to favorably modify the tumor microenvironment, using either single-agent or combination therapy, is an especially appealing therapeutic option for a diverse range of cancers.
引用
收藏
页码:5 / 10
页数:6
相关论文
共 12 条
[1]   Anti-inflammatory properties of the novel antitumor agent yondelis (Trabectedin): Inhibition of macrophage differentiation and cytokine production [J].
Allavena, P ;
Signorelli, M ;
Chieppa, M ;
Erba, E ;
Bianchi, G ;
Marchesi, F ;
Olimpio, CO ;
Bonardi, C ;
Garbi, A ;
Lissoni, A ;
de Brand, F ;
Jimeno, J ;
D'Incalci, M .
CANCER RESEARCH, 2005, 65 (07) :2964-2971
[2]   Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment [J].
Allavena, P. ;
Mantovani, A. .
CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2012, 167 (02) :195-205
[3]   A Review of Trabectedin (ET-743): A Unique Mechanism of Action [J].
D'Incalci, Maurizio ;
Galmarini, Carlos M. .
MOLECULAR CANCER THERAPEUTICS, 2010, 9 (08) :2157-2163
[4]  
Gago Federico, 2004, Current Medicinal Chemistry - Anti-Cancer Agents, V4, P401, DOI 10.2174/1568011043352786
[5]   Role of Macrophage Targeting in the Antitumor Activity of Trabectedin [J].
Germano, Giovanni ;
Frapolli, Roberta ;
Belgiovine, Cristina ;
Anselmo, Achille ;
Pesce, Samantha ;
Liguori, Manuela ;
Erba, Eugenio ;
Uboldi, Sarah ;
Zucchetti, Massimo ;
Pasqualini, Fabio ;
Nebuloni, Manuela ;
van Rooijen, Nico ;
Mortarini, Roberta ;
Beltrame, Luca ;
Marchini, Sergio ;
Nerini, Ilaria Fuso ;
Sanfilippo, Roberta ;
Casali, Paolo G. ;
Pilotti, Silvana ;
Galmarini, Carlos M. ;
Anichini, Andrea ;
Mantovani, Alberto ;
D'Incalci, Maurizio ;
Allavena, Paola .
CANCER CELL, 2013, 23 (02) :249-262
[6]   Targeting of the innate immunity/inflammation as complementary anti-tumor therapies [J].
Germano, Giovanni ;
Mantovani, Alberto ;
Allavena, Paola .
ANNALS OF MEDICINE, 2011, 43 (08) :581-593
[7]   Antitumor and Anti-inflammatory Effects of Trabectedin on Human Myxoid Liposarcoma Cells [J].
Germano, Giovanni ;
Frapolli, Roberta ;
Simone, Matteo ;
Tavecchio, Michele ;
Erba, Eugenio ;
Pesce, Samantha ;
Pasqualini, Fabio ;
Grosso, Federica ;
Sanfilippo, Roberta ;
Casali, Paolo G. ;
Gronchi, Alessandro ;
Virdis, Emanuela ;
Tarantino, Eva ;
Pilotti, Silvana ;
Greco, Angela ;
Nebuloni, Manuela ;
Maria Galmarini, Carlos ;
Carlos Tercero, Juan ;
Mantovani, Alberto ;
D'Incalci, Maurizio ;
Allavena, Paola .
CANCER RESEARCH, 2010, 70 (06) :2235-2244
[8]   Ecteinascidin 743 Interferes with the Activity of EWS-FLI1 in Ewing Sarcoma Cells [J].
Grohar, Patrick J. ;
Griffin, Laurie B. ;
Yeung, Choh ;
Chen, Qing-Rong ;
Pommier, Yves ;
Khanna, Chand ;
Khan, Javed ;
Helman, Lee J. .
NEOPLASIA, 2011, 13 (02) :145-153
[9]   Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma [J].
Grosso, F. ;
Dileo, P. ;
Sanfilippo, R. ;
Stacchiotti, S. ;
Bertulli, R. ;
Piovesan, C. ;
Jimeno, J. ;
D'Incalci, M. ;
Gescher, A. ;
Casali, P. G. .
EUROPEAN JOURNAL OF CANCER, 2006, 42 (10) :1484-1490
[10]   Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study [J].
Grosso, Federica ;
Jones, Robin L. ;
Demetri, George D. ;
Judson, Ian R. ;
Blay, Jean-Yves ;
Le Cesne, Axel ;
Sanfilippo, Roberta ;
Casieri, Paola ;
Collini, Paola ;
Dileo, Palma ;
Spreafico, Carlo ;
Stacchiotti, Silvia ;
Tamborini, Elena ;
Tercero, Juan Carlos ;
Jimeno, Jose ;
D'Incalci, Maurizio ;
Gronchi, Alessandro ;
Fletcher, Jonathan A. ;
Pilotti, Silvana ;
Casali, Paola G. .
LANCET ONCOLOGY, 2007, 8 (07) :595-602