Soft Tissue Sarcoma Knowledge Centre
Management
Novel Therapy - Trabectedin
Mode of Action
Trabectedin (Yondelis®- see prescription information) (trabectedin, formerly know as ET-743 or ecteinascidin) is a novel DNA-binding agent that was originally derived from the marine tunicate Ecteinascidia turbinata, and is now produced synthetically. It consists of three units (tetrahydroisoquinolone rings), as shown in Figure 1, and is an off-white to pale yellow amorphous basic hydrophobic powder.
Fig. 1. Structure of Yondelis®
Reproduced with permission from Scotto (2002) "ET-743: more than an innovative mechanism of action". Anticancer Drugs 13 (Suppl1): S3-6
Trabectedin binds covalently but reversibly to the minor groove of DNA and binds to the N2 atom of the base, guanine, preferably in sequences consisting of purine–G–C and pyrimidine–G–G1. Binding involves two of the units, rings A and B. This bends the DNA towards the major groove (Figure 2), while the C ring protrudes from the DNA backbone and interferes with the binding of other proteins to the DNA2. The anti-tumour effects of Yondelis® are believed to result from this interference in the binding of other proteins to DNA, in particularly transcription factors and DNA-repair proteins3. Yondelis® has been shown to have a number of effects on cells. Firstly, Yondelis® inhibits transcriptional activation of inducible genes, such as c-jun and c-fos4. Since activation of the transcription of specific genes is often important for the abnormal growth of cancer cells, inhibition of this activation can be expected to have an anti-tumour effect. Secondly, Yondelis® has been shown to slow progression of cells through the S phase of the cell cycle and to arrest cells at the G2/Minterphase. This arrest in G2 has been shown to result in p53-independent apoptosis5-7. Cells in G1 phase are the most sensitive to inhibition by Yondelis®8.
Fig. 2. Binding of Yondelis® to the minor groove of DNA makes the helix bend towards the major groove
Reproduced with permission from Zewail-Foote (2001). Copyright Elsevier (2001)
The inhibitory effects of Yondelis® are highly dependent on the presence of two specific DNA-repair systems, known as ‘global genome nucleotide excision repair’ (GG-NER) and ‘transcription-coupled nucleotide excision repair’ (TC-NER). Cells lacking functional GG-NER and/or TC-NER are resistant to the cytotoxic effects of Yondelis®. This is a unique characteristic of Yondelis® since the activity of other DNA-binding cytotoxic agents is either unaffected or decreased by the presence of functional nucleotide excision repair (NER) within the cell9. Yondelis® appears to bind the nucleases involved in these repair mechanisms, thus rendering them inactive and resulting in single-strand breaks in the DNA that are lethal to the cells7,10,11
Summary of Product Characteristics (SmPC)
Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Pharma Mar (contact details below).
Adverse Events Reporting
Pharmacovigilance Department
- Fax: +34 91 846 6004
- Tel: +34 91 846 6055
- e-mail: phv@pharmamar.com
References:
1. Pommier Y, Kohlhagen G et al. (1996) “DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata.” Biochemistry 35(41): 13303–9.
2. Zewail-Foote M, Hurley LH. (1999) “Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove.” J Med Chem 42(14): 2493–97.
3. Fayette J, Coquard IR et al. (2006) ”ET-743: a novel agent with activity in soft tissue sarcomas”. Curr Opin Oncol 18(4): 347–53
4. Minuzzo M, Marchini S et al. (2000) “Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743.” Proc Natl Acad Sci USA 97(12): 6780–84.
5. Erba E, Bergamaschi D et al. (2001) “Ecteinascidin-743 (ET-743), a naturalmarine compound,with a uniquemechanismof action.” Eur J Cancer 37(1): 97–105.
6. Jin S, Gorfajn B et al. (2000) “Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibitsMDR1 activation.” Proc Natl Acad Sci USA 97(12): 6775–79.
7. Takebayashi Y, Goldwasser F et al. (2001a) “Ecteinascidin 743 induces protein-linked DNA breaks in human colon carcinoma HCT116 cells and is cytotoxic independently of topoisomerase I expression.” Clin Cancer Res 7(1): 185–91.
8. Cvetkovic RS, Figgitt DP et al. (2002) “Et-743.” Drugs 62(8): 1185-92.
9. Damia G, Silvestri S et al. (2001) “Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways.” Int J Cancer 92(4): 583–88.
10. Takebayashi Y, Pourquier P et al. (2001b) “Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair.” Nat Med 7(8): 961–66.
11. Zewail-Foote M, Li VS et al. (2001) “The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent.” Chem Biol 8(11): 1033–49.