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 II–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
- D’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.
All treatments for cancer either remove or kill cancer cells. Whether it is surgery, radiation, chemotherapy, or biologic therapy, the goal is to eradicate cancer cells without destroying the patient’s healthy cells. Consider the example of microtubule inhibitors (MTIs)—paclitaxel, eribulin, ixabepilone, and others. All agents in this class affect cancer [ Read More ]
FDA issues finalized guidelines for use of in vitro diagnostics in oncology drug trials and warnings on vaping; new findings report patients bear more costs when MBC treatment is not concordant with NCCN guidelines.