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.
A. DNA replication in a tumour cell. Helicase unwinds DNA, topoisomerase-I makes DNA single-stranded allowing binding of the DNA polymerase. Newly synthesized double-stranded DNA is checked by the DNA repair system for possible mistakes from replication. The nucleotide excision repair (NER) system repairs these mistakes B. Trabectedin disturbs DNA replication by several mechanisms. It consists of three subunits: A and B (yellow and green) bind the DNA; C (blue) interacts with transcription factors (not shown). (1) Trabectedin distorts DNA structure, which prevents binding of proteins essential for replication. (2) Trabectedin cross-links DNA, which causes double-strand breaks (DSB). (3) In interaction with an active nucleotide excision repair (NER) site, trabectedin also causes DSB
Available at http://www.emea.europa.eu/humandocs/Humans/EPAR/yondelis/yondelis.htm
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. doi: 10.1158/0008-5472.CAN-06-0179. [DOI] [PubMed] [Google Scholar]