Mechanism of Action Magnifier – 2016 Desk Reference
Trabectedin: a DNA-Binding Agent That Covalently Interacts with the Minor Groove of the DNA Double Helix
Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by 3 fused tetrahydroisoquinoline rings.1
Trabectedin binds to the minor groove of DNA and alkylates guanine at the N2 position, bending the helix toward the major groove.2,3 In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system.3
In addition, this binding to DNA triggers a cascade of events affecting DNA binding proteins and DNA repair pathways, resulting in perturbation of the cell cycle.1,2 Trabectedin blocks the cell cycle at the G(2) phase, while cells at the G(1) phase are most sensitive to the drug.3
Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment.1
One of the most novel aspects of trabectedin is its effect on RNA polymerase IIâ€“mediated gene transcription.4 Trabectedin inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs.3 Trabectedin selectively inhibits activation of the MDR-1, while leaving constitutive gene expression relatively unaffected.4
- Dâ€™Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010;9:2157-2163.
- Yondelis (trabectedin) product monograph. Toronto, Ontario, Canada: Janssen Inc; 2011.
- Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766. Drugs R D. 2006;7:317-328.
- Scotto KW. ET-743: more than an innovative mechanism of action. Anticancer Drugs. 2002;13(suppl 1):S3-S6.
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The immune system recognizes and is poised to eliminate cancer but is held in check by a plethora of inhibitory pathways that regulate cellular immune responses.1 These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during antimicrobial immune responses, can be co-opted by cancer to evade [ Read More ]
2021 Midyear Review: Nonâ€“Small-Cell Lung Cancer
Researchers and clinicians continue to make advances in the treatment of cancer. In 2021, despite the COVID-19 pandemic, there have been many exciting developments in biomarker testing and other diagnostics, treatment approaches and targets, and other aspects of cancer care.