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Titolo:
PHASE IB STUDY OF DOXORUBICIN IN COMBINATION WITH THE MULTIDRUG-RESISTANCE REVERSING AGENT S9788 IN ADVANCED COLORECTAL AND RENAL-CELL CANCER
Autore:
PUNT CJA; VOEST EE; TUENI E; VANOOSTEROM AT; BACKX A; DEMULDER PHM; HECQUET B; LUCAS C; GERARD B; BLEIBERG H;
Indirizzi:
UNIV NIJMEGEN HOSP,DEPT MED ONCOL,POB 9101 NL-6500 HB NIJMEGEN NETHERLANDS UNIV NIJMEGEN HOSP,DEPT CARDIOL NL-6500 HB NIJMEGEN NETHERLANDS UNIV UTRECHT HOSP,DEPT INTERNAL MED UTRECHT NETHERLANDS JOLIMONT HOSP TIVOLI BELGIUM UNIV ANTWERP HOSP,DEPT MED ONCOL ANTWERP BELGIUM CTR OSCAR LAMBRET F-59020 LILLE FRANCE IRI SERVIER COURBEVOIE FRANCE INST JULES BORDET B-1000 BRUSSELS BELGIUM
Titolo Testata:
British Journal of Cancer
fascicolo: 10, volume: 76, anno: 1997,
pagine: 1376 - 1381
SICI:
0007-0920(1997)76:10<1376:PISODI>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
QT INTERVAL PROLONGATION; P-GLYCOPROTEIN; DRUG-RESISTANCE; CYCLOSPORINE-A; IN-VITRO; VERAPAMIL; CARCINOMA; CIRCUMVENTION; EXPRESSION; INVIVO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
37
Recensione:
Indirizzi per estratti:
Citazione:
C.J.A. Punt et al., "PHASE IB STUDY OF DOXORUBICIN IN COMBINATION WITH THE MULTIDRUG-RESISTANCE REVERSING AGENT S9788 IN ADVANCED COLORECTAL AND RENAL-CELL CANCER", British Journal of Cancer, 76(10), 1997, pp. 1376-1381

Abstract

S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m(-2)over 30 min followed by doxorubicin given at 50 mg m(-2) as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m(-2) in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced asignificant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Hotter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severecardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/11/20 alle ore 19:34:40