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Titolo:
Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial
Autore:
Karp, JE; Lancet, JE; Kaufmann, SH; End, DW; Wright, JJ; Bol, K; Horak, I; Tidwell, ML; Liesveld, J; Kottke, TJ; Ange, D; Buddharaju, L; Gojo, I; Highsmith, WE; Belly, RT; Hohl, RJ; Rybak, ME; Thibault, A; Rosenblatt, J;
Indirizzi:
Univ Maryland, Greenbaum Canc Ctr, Baltimore, MD 21201 USA Univ Maryland Baltimore MD USA 21201 um Canc Ctr, Baltimore, MD 21201 USA Univ Rochester, Ctr Canc, Rochester, NY USA Univ Rochester Rochester NY USA v Rochester, Ctr Canc, Rochester, NY USA Mayo Clin, Rochester, MN USA Mayo Clin Rochester MN USAMayo Clin, Rochester, MN USA Janssen Res Fdn, B-2340 Beerse, Belgium Janssen Res Fdn Beerse Belgium B-2340 en Res Fdn, B-2340 Beerse, Belgium Janssen Res Fdn, Spring House, PA 19477 USA Janssen Res Fdn Spring House PA USA 19477 Fdn, Spring House, PA 19477 USA NCI, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892NCI, Bethesda, MD 20892 USA Ortho Clin Diagnost, Rochester, NY USA Ortho Clin Diagnost Rochester NY USA ho Clin Diagnost, Rochester, NY USA Univ Iowa, Iowa City, IA USA Univ Iowa Iowa City IA USAUniv Iowa, Iowa City, IA USA
Titolo Testata:
BLOOD
fascicolo: 11, volume: 97, anno: 2001,
pagine: 3361 - 3369
SICI:
0006-4971(20010601)97:11<3361:CABAOT>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; SIGNAL-TRANSDUCTION; RAS MUTATIONS; LAMIN-A; PROTEIN; CANCER; GENE; DAUNORUBICIN; MECHANISMS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
55
Recensione:
Indirizzi per estratti:
Indirizzo: Karp, JE Univ Maryland, Greenbaum Canc Ctr, 22 S Greene St,Rm S9D07, Baltimore, MD 21201 USA Univ Maryland 22 S Greene St,Rm S9D07 Baltimore MD USA 21201 USA
Citazione:
J.E. Karp et al., "Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial", BLOOD, 97(11), 2001, pp. 3361-3369

Abstract

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models, This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days, Dose-limitingtoxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria, Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression, R115777 inhibited FT activity at 300 mg bid and farnesylation ofFT substrates lamin A and HDJ-2 at 600 mg bid, Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration, Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions, Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias, The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity. (Blood, 2001;97:3361-3369) (C) 2001 by The American Society of Hematology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 15:41:15