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.
In my medical oncology practice at Johns Hopkins, I see approximately 4 patients with nonmetastatic NSCLC per week. Most of these patients are referrals from either pulmonary medicine or thoracic surgery. A patient with early stage disease initially sees a pulmonologist for diagnosis and may then be referred to a thoracic surgeon. The thoracic surgeon may refer the patient to us in medical oncology if there is an indication to enroll the patient in a clinical trial or for systemic therapy. In a community oncology practice, patients tend to go to surgery first and are then referred to the medical oncologist for adjuvant chemotherapy. In academic centers, it is more common for patients to be seen in a multidisciplinary setting.
One question on oncologists’ minds recently is whether treatment with immune checkpoint inhibitors in patients with cancer has a negative effect on COVID-19 disease. So far, the data have not shown a deleterious effect, but the definitive answer is unknown. In fact, some experts think immune checkpoint inhibitors may have a positive effect on the virus.