Mechanism of Action Magnifier – 2016 Desk Reference

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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

References

  1. D’Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010;9:2157-2163.
  2. Yondelis (trabectedin) product monograph. Toronto, Ontario, Canada: Janssen Inc; 2011.
  3. Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766. Drugs R D. 2006;7:317-328.
  4. Scotto KW. ET-743: more than an innovative mechanism of action. Anticancer Drugs. 2002;13(suppl 1):S3-S6.
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TLR9 Agonist plus Immunotherapy May Overcome Resistance to PD-1 Inhibition

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Ruxolitinib: a Kinase Inhibitor That Inhibits Overactive JAK Pathway Signaling

Overactive JAK pathway signaling is a key mechanism of disease in the myeloproliferative neoplasms (MPNs) polycythemia vera and myelofibrosis.1,2 Signaling of the JAK pathway plays a key role in normal cell functioning.3-6 Well-regulated JAK signaling is essential for cell production, cell proliferation, and immune function. Intracellular regulators, such as suppressor [ Read More ]