Drugs

, Volume 62, Issue 8, pp 1185–1192

ET-743

  • Risto S. Cvetkovic
  • David P. Figgitt
  • Greg L. Plosker
Adis New Drug Profile

Abstract

  • ▴ ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas.

  • ▴ The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo.

  • ▴ The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second-or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months.

  • ▴ A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%.

  • ▴ ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.

References

  1. 1.
    Brennan MF, Casper ES, Harrison LB. Soft tissue sarcoma. In: DeVita Jr VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers, 1997: 1738–88Google Scholar
  2. 2.
    Mouridsen HT, Bastholt L, Somers R, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas: a randomized phase II/phase III study of EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol 1987; 23: 1477–83PubMedCrossRefGoogle Scholar
  3. 3.
    Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995 Jul; 13: 1537–45PubMedGoogle Scholar
  4. 4.
    Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987 Jun; 5: 840–50PubMedGoogle Scholar
  5. 5.
    Borden EC, Amato DA, Edmonson JH, et al. Randomized comparison of doxorubicin and vindesine to doxorubicin for patients with metastatic soft-tissue sarcomas. Cancer 1990; 66: 862–7PubMedCrossRefGoogle Scholar
  6. 6.
    Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin or cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993 Jul; 11: 1269–75PubMedGoogle Scholar
  7. 7.
    Bramwell VHC, Mouridsen HT, Santoro A, et al. Cyclophosphamide versus ifosfamide: a randomized phase II trial in adult soft-tissue sarcomas. Cancer Chemother Pharmacol 1993; 31 Suppl. 2: S180–4PubMedGoogle Scholar
  8. 8.
    Demetri GD, Elias AD. Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am 1995 Aug; 9(4): 765–85PubMedGoogle Scholar
  9. 9.
    Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL / CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001; 37: 870–7PubMedCrossRefGoogle Scholar
  10. 10.
    Pommier Y, Kohlhagen G, Bailly C, et al. 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 (Mosc) 1996; 35: 13303–9CrossRefGoogle Scholar
  11. 11.
    Moore II BM, Seaman FC, Hurley LH. NMR-based model of an ecteinascidin 743-DNA adduct. J Am Chem Soc 1997; 199: 5475–6CrossRefGoogle Scholar
  12. 12.
    Zewail-Foote M, Hurley LH. Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 1999 Jul 15; 42(14): 2493–7PubMedCrossRefGoogle Scholar
  13. 13.
    Garcia-Nieto R, Manzanares I, Cuevas C, et al. Bending of DNA upon binding of ecteinascidin 743 and phthalascidin 650 studied by unrestrained molecular dynamics simulations. J Am Chem Soc 2000; 122(30): 7172–82CrossRefGoogle Scholar
  14. 14.
    Rinehart KL, Holt TG, Fregeau NL, et al. Ecteinascidins 729, 743, 745, 759A, 759B and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem 1990; 55: 4512–5CrossRefGoogle Scholar
  15. 15.
    Sakai R, Jares-Erijman EA, Manzanares I, et al. Ecteinascidins: putative biosynthetic precursors and absolute stereochemistry. J Am Chem Soc 1996; 118(38): 9017–23CrossRefGoogle Scholar
  16. 16.
    Takebayashi Y, Pourquier P, Zimonjic DB, et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001 Aug; 7(8): 961–6PubMedCrossRefGoogle Scholar
  17. 17.
    Zewail-Foote M, Li VS, Kohn H, et al. 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 2001 Nov; 8(11): 1033–49PubMedCrossRefGoogle Scholar
  18. 18.
    Damia G, Silvestri S, Carrassa L, et al. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer 2001 May 15; 92(4): 583–8PubMedCrossRefGoogle Scholar
  19. 19.
    Takebayashi Y, Goldwasser F, Urasaki Y, et al. Ecteinascidin 743 induces protein-linked DNA breaks in human colon carcinoma HCT116 cells and is cytotoxic independently of topoisomerase I expression. Clin Cancer Res 2001 Jan; 7(1): 185–91PubMedGoogle Scholar
  20. 20.
    Jin S, Gorfajn B, Faircloth G, et al. Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc Natl Acad Sci U S A 2000 Jun 6; 97(12): 6775–9PubMedCrossRefGoogle Scholar
  21. 21.
    Erba E, Bergamaschi D, Bassano L, et al. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 2001 Jan; 37(1): 97–105PubMedCrossRefGoogle Scholar
  22. 22.
    Minuzzo M, Marchini S, Broggini M, et al. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci U S A 2000 Jun 6; 97(12): 6780–4PubMedCrossRefGoogle Scholar
  23. 23.
    Perdichizzi S, Manara MC, Serra M, et al. Effectiveness of the antineoplastic drug ecteinascidin-743 on sensitive and multi-drug resitant osteosarcoma cells [abstract]. Tumori 2001 Jul-2001 31; 87 Suppl. 2: 86–7Google Scholar
  24. 24.
    Li W, Jhanwar S, Elisseyeff Y, et al. Potent antitumor activity of ET-743 against human soft tissue sarcoma cell lines [abstract]. Clin Cancer Res 1999 Nov; 5 Suppl.: 3790sGoogle Scholar
  25. 25.
    Shtil AA, Kolb EA, Faircloth G, et al. Ecteinascidin 743, a novel natural cytotoxic compound, is potent for human neuroblastoma and rhabdomyosarcoma cell lines: multiple mechanisms of cell kill [abstract]. 92nd Annu Meet Am Assoc Cancer Res 2001 Mar; New Orleans. 42: 811Google Scholar
  26. 26.
    Eckhardt SG, Degen D, Ortiz V, et al. In vitro studies of a novel marine cytotoxic, ecteinascidin (ET-743). Ann Oncol 1996; 7 Suppl. 5: 131CrossRefGoogle Scholar
  27. 27.
    Erba E, Bergamaschi D, Ronzoni S, et al. Mode of action of Ecteinascidin 743, a natural marine compound with antitumoral activity [abstract]. Ann Oncol 1998; 9 Suppl. 2: 139CrossRefGoogle Scholar
  28. 28.
    Faircloth G, Avila J, Fernandez Puentes JL, et al. Ecteinascidin (ET) 743: developmental status of a marine (M) derived anticancer compound (AC) [abstract]. Eur J Cancer A 1995; 31A Suppl. 5: S26–7CrossRefGoogle Scholar
  29. 29.
    Faircloth G, Cameron L, D’Incalci M, et al. Ecteinascidin-743 (ET743): in vitro (IVT) and in vivo (INV) results in solid tumor models [abstract]. Eur J Cancer A 1996; 32A Suppl. 1: S5CrossRefGoogle Scholar
  30. 30.
    Ghielmini M, Colli E, Erba E, et al. In vitro schedule-dependency of myelotoxicity and cytotoxicity of Ecteinascidin 743 (ET-743). Ann Oncol 1998 Sep; 9(9): 989–93PubMedCrossRefGoogle Scholar
  31. 31.
    Garcia Gravalos MD, Ruiz Lazaro P, Faircloth GT, et al. In vitro schedule-dependent cytotoxicity by ecteinascidin 743 (ET 743) against human tumor cells [abstract]. Ann Oncol 1998; 9 Suppl. 4: 136Google Scholar
  32. 32.
    Izbicka E, Lawrence R, Raymond E, et al. In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 1998 Sep; 9(9): 981–7PubMedCrossRefGoogle Scholar
  33. 33.
    Valoti G, Nicoletti MI, Pellegrino A, et al. Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts. Clin Cancer Res 1998 Aug; 4(8): 1977–83PubMedGoogle Scholar
  34. 34.
    Hendriks HR, Fiebig HH, Giavazzi R, et al. High antitumour activity of ET743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer. Ann Oncol 1999 Oct; 10(10): 1233–40PubMedCrossRefGoogle Scholar
  35. 35.
    Chi KH, Chao Y, Wang SM, et al. Evaluation of ecteinascidin-743 (ET-743) against human hepatoma in vitro and as xenografts in nude mice [abstract]. 90th Annu Meet Am Assoc Cancer Res 1999 Apr 10; Philadelphia. 344Google Scholar
  36. 36.
    Li WW, Takahashi N, Jhanwar S, et al. Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of ecteinascidin-743 as a potent cytotoxic agent. Clin Cancer Res 2001 Sep; 7(9): 2908–11PubMedGoogle Scholar
  37. 37.
    Chan HSL, Thorner PS, Haddad G, et al. Immunochistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma in childhood. J Clin Oncol 1990 Apr; 8: 689–704PubMedGoogle Scholar
  38. 38.
    Baldini N, Scotlandi K, Barbanti-Brodano G, et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. NEJM 1995 Nov 23; 333: 1380–5PubMedCrossRefGoogle Scholar
  39. 39.
    Abolhoda A, Wilson AE, Ross H, et al. Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clin Cancer Res 1999 Nov; 5: 3352–6PubMedGoogle Scholar
  40. 40.
    Takahashi N, Li WW, Banerjee D, et al. Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Cancer Res 2001 Oct; 7(10): 3251–7PubMedGoogle Scholar
  41. 41.
    Villalona-Calero M, Eckhardt SG, Hammond L, et al. Final results of a phase I and pharmacokinetic (PK) study of the marine minor groove binder ET-743 on a daily × 5 schedule [abstract]. 35th Proc Am Soc Clin Oncol 1999 May 15; Atlanta. 18: 180aGoogle Scholar
  42. 42.
    Bowman A, Twelves C, Hoekman K, et al. Phase I clinical and pharmacokinetic study (PK) of ecteinascidin-743 (ET-743) given as a one hour infusion every 21 days [abstract]. Ann Oncol 1998; 9 Suppl. 2: 118Google Scholar
  43. 43.
    Twelves C, Hoeckman H, Bowman A, et al. A phase I and pharmacokinetic (PK) study of ET-743 evaluating a 3 hours (h) intravenous (iv) infusion (I) in patients (pts) with solid tumors [abstract]. Clin Cancer Res 1999 Nov; 5 Suppl.: 3790–3791sGoogle Scholar
  44. 44.
    van Kesteren C, Cvitkovic E, Taamma A, et al. Pharmacokinetics and pharmacodynamics of the novel marine-derived anti-cancer agent ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res 2000 Dec; 6(12): 4725–32PubMedGoogle Scholar
  45. 45.
    Ryan DP, Supko JG, Eder JP, et al. Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies. Clin Cancer Res 2001 Feb; 7(2): 231–42PubMedGoogle Scholar
  46. 46.
    Beijnen JH, Rosing H, Cvitkovic E, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of ET-743 (ecteinascidin-743) in phase I trials [abstract]. 35th Proc Am Soc Clin Oncol 1999 May 15; 18: 163Google Scholar
  47. 47.
    Beijnen HJ. Pharmacokinetic parameters: predictive factors for ET-743 tolerability/safety profile [abstract]. 11th European Cancer Conference Satellite Symposium; 2001 Oct 21–25; LisbonGoogle Scholar
  48. 48.
    Lopez-Lazaro L, van Kesteren C, Hoekman K, et al. Ecteinascidin (ET-743) pharmacokinetics (PK): overview of phase I and advanced phase II results [abstract]. Eur J Cancer 2001 Oct; 37 Suppl. 6: S66CrossRefGoogle Scholar
  49. 49.
    Kuffel MJ, Reid JM, Ames MM. Cytochrome P450 catalyzed metabolism of Ecteinascidin 743 by rat and human liver microsomes [abstract]. 88 th Annual Meeting of American Association for Cancer Research; 1997 Apr 12; San Diego (CA), 596Google Scholar
  50. 50.
    Reid JM, Kuffel MJ, Squillace DP, et al. Characterization of the in vitro metabolism, pharmacokinetics, and biliary excretion of Ecteinascidin 743 (NSC 648766) in male and female rats [abstract]. Ann Oncol 1998; 9 Suppl. 2: 50Google Scholar
  51. 51.
    Sparidans RW, Rosing H, Hillebrand MJXL-LL, et al. Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man. Anticancer Drugs 2001 Sep; 12(8): 653–66PubMedCrossRefGoogle Scholar
  52. 52.
    Demetri GD, Manola J, Harmon D, et al. Ecteinascidin-743 (ET-743) induces durable responses and promising 1-year survival rates in soft tissue sarcomas STS): final results of phase II and pharmacokinetic studies in the U.S.A [abstract]. 37th Annual Meeting of the American Society of Clinical Oncology 2001 May 12; San Francisco 20 (Part 1): 352Google Scholar
  53. 53.
    Le Cesne A. ET-743: The EORTC Experience [abstract]. 11th European Cancer Conference Satellite Symposium; 2001 Oct 21–25; LisbonGoogle Scholar
  54. 54.
    Brain EGC. Safety and efficacy of ET-743: the French experience [abstract]. 11th European Cancer Conference Satellite Symposium; 2001 Oct 21–25; LisbonGoogle Scholar
  55. 55.
    Le Cesne A, Misset JL, Demetri G, et al. Consistent evidence of activity of ecteinascidin (ET-743) in pretreated, advanced soft tissue sarcoma (ASTS): results from a pooled analysis of three pivotal phase II clinical trials (p2ct) and safety profile of a 24 h infusion schedule [abstract]. Eur J Cancer 2001 Oct; 37 Suppl. 6: S34CrossRefGoogle Scholar
  56. 56.
    Le Cesne A, Blay J, Judson I, et al. Ecteinascidin (ET-743) is an active drug in adult soft-tissue sarcoma (STS): a STBSG-EORTC phase II trial [abstract]. 37th Annual Meeting of the American Society of Clinical Oncology 2001 May 12; San Francisco. 20 (Part 1): 353aGoogle Scholar
  57. 57.
    Yovine A, Riofrio M, Brain E, et al. Ecteinascidin (ET-743) given as a 24 hour (h) intravenous continuous infusion (IVCI) every 3 weeks: results of a phase II trial in patients (pts) with pretreated soft tissue sarcomas (PSTS) [abtsract]. 37th Annual Meeting of the American Society of Clinical Oncology 2001 May 12; San Francisco. 20 (Part 1): 363aGoogle Scholar
  58. 58.
    Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981 Jan; 47: 207–14PubMedCrossRefGoogle Scholar
  59. 59.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000 Feb 2; 92(3): 205–16PubMedCrossRefGoogle Scholar
  60. 60.
    Conlon KC, Casper ES, Brennan MF. Primary gastrointestinal sarcomas: analysis of prognostic variables. Ann Surg Oncol 1995 Jan; 2(1): 26–31PubMedCrossRefGoogle Scholar
  61. 61.
    Gomez J, Lopez Lazaro L, Guzman C, et al. Identification of biochemical parameters that predict the onset of severe toxicities in patients treated with ET-743 [abstract]. 36th Proc Am Soc Clin Oncol 2000 May 20; New Orleans. 19: 187aGoogle Scholar
  62. 62.
    Forouzesh B, Hidalgo M, Denis L, et al. Phase I and pharmacokinetic study of ET-743, a minor groove DNA binder, administered weekly to patients with advanced cancer [abstract]. Eur J Cancer 2001 Oct; 37 Suppl. 6: S32CrossRefGoogle Scholar
  63. 63.
    Zelek L, Yovine A, Brain E, et al. Ecteinascidin-743 (ET-743) in taxane (T)/anthracycline (A) pretreated advanced/metastatic breast cancer (A/MBC) patients (pts): preliminary results with the 24 hour (h) continuous infusion (CI) q3week schedule [abstract]. 36th Proc Am Soc Clin Oncol 2000 May 20; New Orleans. 19: 149aGoogle Scholar
  64. 64.
    Zelek L, Yovine A, Brain E, et al. Preliminary results of phase II study of ecteinascidin-743 (ET-743) with the 24 hour (H) continuous infusion (CI) q3week schedule in pretreated advanced/metastatic breast cancer (A/MBC) patients (pts) [abstract]. 11th Symposium on New Drugs in Cancer Therapy 2000 Nov 7–10, Amsterdam. 85-6Google Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Risto S. Cvetkovic
    • 1
  • David P. Figgitt
    • 1
  • Greg L. Plosker
    • 1
  1. 1.Adis International LimitedAucklandNew Zealand

Personalised recommendations