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Titolo:
Phase I and pharmacokinetic study of esteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies
Autore:
Ryan, DP; Supko, JG; Eder, JP; Seiden, MV; Demetri, G; Lynch, TJ; Fischman, AJ; Davis, J; Jimeno, J; Clark, JW;
Indirizzi:
Massachusetts Gen Hosp, Boston, MA 02114 USA Massachusetts Gen Hosp Boston MA USA 02114 Gen Hosp, Boston, MA 02114 USA Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA HarvardUniv Boston MA USA 02115 a Farber Canc Inst, Boston, MA 02115 USA Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 Gen Hosp, Sch Med, Boston, MA 02115 USA Pharm Mar S A, Clin Res & Dev, Madrid, Spain Pharm Mar S A Madrid SpainPharm Mar S A, Clin Res & Dev, Madrid, Spain
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 2, volume: 7, anno: 2001,
pagine: 231 - 242
SICI:
1078-0432(200102)7:2<231:PIAPSO>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERFORMANCE LIQUID-CHROMATOGRAPHY; TUNICATE ECTEINASCIDIA-TURBINATA; POTENT ANTITUMOR-ACTIVITY; MARINE NATURAL PRODUCT; CARIBBEAN TUNICATE; CRYSTAL-STRUCTURES; ANTICANCER DRUG; MINOR-GROOVE; HUMAN PLASMA; GUANINE N2;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Ryan, DP Massachusetts Gen Hosp, 55 Fruit St,Cox Bldg,Room 640, Boston, MA02114 USA Massachusetts Gen Hosp 55 Fruit St,Cox Bldg,Room 640 Boston MA USA 02114
Citazione:
D.P. Ryan et al., "Phase I and pharmacokinetic study of esteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies", CLIN CANC R, 7(2), 2001, pp. 231-242

Abstract

Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline alkaloid that covalently binds to DNA in the minor groove. The ill vitro chemosensitivity of cancer cells to ET-743 is markedly enhanced by prolonging the duration of exposure to the drug. A Phase I study of ET-743 given as a 72-h continuous i.v. infusion every 21 days was performed. Characteristics of the 21 adult patients with refractory solid tumors enrolled in the study were asfollows: (a) 12 men; (b) 9 women; (c) median age, 59 years; (d) Eastern Cooperative Oncology Group performance status less than or equal to1, 20 patients; and (e) two prior regimens of chemotherapy, 7 patients. Dose limitingtoxicity (DLT) was defined by typical criteria, except that grade 3 transaminitis did not constitute a DLT, There were no DLTs in the six patients evaluated at the first two dose levels of 600 and 900 mug/m(2), Reversible grade 4 transaminitis occurred in two of nine patients after treatment with the first cycle of therapy at the third dose level of 1200 mug/m(2). Anotherpatient experienced grade 4 rhabdomyolysis, renal failure requiring hemodialysis, grade 4 neutropenia, and grade 3 thrombocytopenia during the secondcycle of therapy with this dose. The maximum tolerated dose was 1200 mug/m(2), and an additional six patients were enrolled at an intermediate dose level of 1050 mug/m(2). This well-tolerated dose was established as the recommended Phase II dose. The disposition of ET-743 was distinctly biexponential, and a departure from linear pharmacokinetic behavior was evident at the1200-mug/m(2) dose level. Pharmacokinetic parameters determined at 1050 mug/m(2) were (mean +/- SD): maximum plasma concentration, 318 +/- 147 pg/ml;initial disposition phase half-life, 9.0 +/- 10.3 min; terminal phase half-life, 69.0 +/- 56.7 h; and total plasma clearance, 28.4 +/- 22.5 liters/h/m(2). Prolonged systemic exposure to concentrations of the agent that are cytotoxic in vitro were achieved. Toxicity of the drug is clearly schedule-dependent, because increasing the duration of infusion from 3 or 24 h to 72 h results in decreased myelosuppression and comparable hepatotoxicity, Although there were no objective responses to therapy, clear evidence of antitumor activity was observed in a patient with epithelioid mesothelioma, as confirmed by positron emission tomography studies. A Phase II trial to assessthe efficacy of ET-743 against this highly refractory neoplasm has been initiated on the basis of this observation. The therapeutically optimal administration schedule remains to be established, inasmuch as there have been indications of activity against a variety of tumors during Phase I studies when the drug was infused over times ranging from 1 to 72 h, Characterizing the pharmacokinetics of ET-743 during the course of Phase II trials and Phase I combination studies is recommended to assure that this promising new anticancer drug can be used with an acceptable margin of safety.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/10/20 alle ore 11:28:42