ET-743

[Jana4]

Ich habe eine Frage bezüglichs des Medikaments ET-743. Wie wirkt es? Für welche Krebsarten kommt es in Frage? Wann kommt es auf den deutschen Markt? Kann man sich in schwierigen Fällen als Probant melden?

Vielen, vielen Dank!

[Tiger 2002]

RE: ET-743


Hallo Jana,

ET-743 wirkt vor allem bei Tumoren des Bindegewebes (Weichteilsarkomen) eingesetzt.Aber auch bei Brustkrebs im fortgeschrittenem Stadium scheint ET-743 anzuschlagen.Es laufen derzeit noch Studien (oder sind bereits abgeschlossen) ob es evtl auch bei Bauchspeicheldrüsenkrebs,Bronchialkarzinom und Speiseröhrenkrebs wirksam ist.
Auf jeden Fall wird es für imindesten 14 Tumorarten geprüft.

Die Wirkung von ET-743 beruht darauf das den sogenannten NER Mechanismus (Nukleotid Excision Reparatur) nutzt
Bei dieser Reperatur werden werden fehlerhafte DNS Bausteine aus der Erbgut Sequenz einer Zelle herausgeschnitten.Et-743 heftet sich dabei an die DNS und es kommt so zum Zelltod.
Es laufen bereits klinische Studien der Phase 2 und 3 (Stand Ende 2001) Es wird also,so denke ich ,nicht mehr lange dauern bis man genaueres weis.
Ob man noch daran teil nehmen kann,ist mir nicht bekannt.Vielleicht kann ihnen da Prof.Wust weiter helfen.

Gruß
Michael Dorsch

[Prof. Wust]

RE: ET-743


Wie Sie an den Zusammenfassungen (s.u.) sehen, ist das Medikament gerade in einer Phase I Prüfung. So spektakulär scheinen mir die Ergebnisse bisher nicht. Unter www.studien.de ist es nicht zu finden. Versuchen Sie den Hersteller herauszufinden. Dort können Sie am besten fragen, ob Studien laufen und wie die Eingangskriterien sind. Mehr weiß ich leider auch nicht.

Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways.
Damia,-G; Silvestri,-S; Carrassa,-L; Filiberti,-L; Faircloth,-G-T; Liberi,-G; Foiani,-M; D'Incalci,-M
AD: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. [email protected]
SO: Int-J-Cancer. 2001 May 15; 92(4): 583-8
AB: The cytotoxic activity of ecteinascidin 743 (ET-743), a natural product derived from the marine tunicate Ecteinascidia turbinata that exhibits potent anti-tumor activity in pre-clinical systems and promising activity in phase I and II clinical trials, was investigated in a number of cell systems with well-defined deficiencies in DNA-repair mechanisms. ET-743 binds to N2 of guanine in the minor groove, but its activity does not appear to be related to DNA-topoisomerase I poisoning as the drug is equally active in wild-type yeast and in yeast with a deletion in the DNA-topoisomerase I gene. Defects in the mismatch repair pathway, usually associated with increased resistance to methylating agents and cisplatin, did not affect the cytotoxic activity of ET-743. However, ET-743 did show decreased activity (from 2- to 8-fold) in nucleotide excision repair (NER)-deficient cell lines compared to NER-proficient cell lines, from either hamsters or humans. Restoration of NER function sensitized cells to ET-743 treatment. The DNA double-strand-break repair pathway was also investigated using human glioblastoma cell lines MO59K and MO59J, respectively, proficient and deficient in DNA-dependent protein kinase (DNA-PK). ET-743 was more effective in cells lacking DNA-PK; moreover, pre-treatment of HCT-116 colon carcinoma cells with wortmannin, a potent inhibitor of DNA-PK, sensitized cells to ET-743. An increase in ET-743 sensitivity was also observed in ataxia telangiectasia-mutated cells. Our data strongly suggest that ET-743 has a unique mechanism of interaction with DNA.

Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors.
AU: Taamma,-A; Misset,-J-L; Riofrio,-M; Guzman,-C; Brain,-E; Lopez-Lazaro,-L; Rosing,-H; Jimeno,-J-M; Cvitkovic,-E
AD: Hopital Paul Brousse, Villejuif, France.
SO: J-Clin-Oncol. 2001 Mar 1; 19(5): 1256-65
AB: PURPOSE: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors. PATIENTS AND METHODS: Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 microg/m(2). RESULTS: The MTD was defined as 1,800 microg/m(2) (DL 9), and the phase II RD was 1,500 microg/m(2) (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 microg/m(2)) in 94% and 25% of cycles, respectively. At the RD (1,500 microg/m(2)), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting > or = 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood. CONCLUSION: The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 microg/m(2), with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.