Trabectedin Mechanism of Action

Indication

Trabectedin is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of other cytostatic agents.

Mechanism

Trabectedin is an alkylating cytostatic drug derived from a Caribbean tunicate. Its action is incompletely understood, but differs from that of traditional alkylating agents. Trabectedin consists of three subunits, A, B and C, of which A and B bind DNA and C interacts with transcription factors.

DNA binding of trabectedin:

• distorts DNA structure, preventing interaction with DNA binding proteins that is essential for DNA replication.

• cross-links DNA, preventing topoisomerase-I from opening the DNA and hindering attachment of DNA polymerase with subsequent failure of replication.

• disrupts the so-called nucleotide excision repair (NER) system. This NER system discovers mistakes in DNA that have arisen during replication. Trabectedin causes double strand breaks at an active NER site.

Trabectidin binding via the C subunit also:

• inhibits transcription of several genes, including the multiple drug resistance-1 gene, which expresses membrane transporters that pump cytostatic drugs out of tumour cells.

Adverse effects

Several adverse effects of trabectedin can be deduced from its pharmacological actions and are very similar to those of other cytostatics, including emesis, vomiting, myelosuppression and liver toxicity.

Literature

Herrero, AB, Martín-Castellanos, C, Marco, E, Gago, F, Moreno, S. Cross-talk between nucleotide excision and homologous recombination DNA repair pathways in the mechanism of action of antitumor trabectedin. Cancer Res 2006; 66: 8155–62.

Available at http://www.emea.europa.eu/humandocs/Humans/EPAR/yondelis/yondelis.htm