Trabectedin

Trabectedin

Trabectedin is new alkylating cytostatic drug derived from a Caribbean tunicate with a different mechanism of action compared to that of the traditional alkylating agents. Although the entire mechanism of action has not been elucidated yet, some mechanisms have been determined. Trabectedin consists of 3 subunits of which A and B bind the DNA and C is involved in the interaction with transcription factors. DNA binding of trabectedin leads to a distortion of the DNA structure, which prevents interaction of all kinds of DNA binding proteins essential for DNA replication. Another mechanism involves cross-linking of DNA. The topomerase I enzyme is not able of unwinding cross-linked DNA and subsequently the DNA polymerase cannot attach resulting in failure of replication. A last mechanism of trabectedin depends on the effectivity of the so-called nucleotide excision repair (NER) system. This NER system discovers

mistakes in the DNA occurring during the replication process. Trabectedin causes double strand breaks (DSB) at an active NER site.

Besides all mechanisms that require DNA binding, there also is a therapeutic effect caused by the C subunit of trabectedin. This subunit inhibits the transcription of several genes. An example of such an inactivated gene is the multiple drug resistance-1 gene (MDR1), which expresses membrane transporters that pump cytostatics out of tumor cells.

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

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

EPAR of trabectedin. This drug has been withdrawn from the EMA authorised drug list.