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Titolo:
DIPHTHERIA-TOXIN FUSED TO GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IS TOXIC TO BLASTS FROM PATIENTS WITH JUVENILE MYELOMONOCYTIC LEUKEMIA AND CHRONIC MYELOMONOCYTIC LEUKEMIA
Autore:
FRANKEL AE; LILLY M; KREITMAN R; HOGGE D; BERAN M; FREEDMAN MH; EMANUEL PD; MCLAIN C; HALL P; TAGGE E; BERGER M; EAVES C;
Indirizzi:
WAKE FOREST UNIV,BOWMAN GRAY SCH MED,CTR COMPREHENS CANC,HANES 4046,MED CTR DR WINSTON SALEM NC 27157 UNIV WASHINGTON,DEPT MED,DIV MED ONCOL SEATTLE WA 00000 NCI,MOL BIOL LAB,NIH BETHESDA MD 20892 BRITISH COLUMBIA CANC AGCY,TERRY FOX LAB VANCOUVER BC V5Z 1L3 CANADA UNIV TEXAS,MD ANDERSON CANCER CTR,LEUKEMIA DEPT HOUSTON TX 77030 HOSP SICK CHILDREN,DIV HEMATOL ONCOL TORONTO ON M5G 1X8 CANADA UNIV ALABAMA,CTR COMPREHENS CANC BIRMINGHAM AL 35294 MED UNIV S CAROLINA,DEPT SURG CHARLESTON SC 29425 MED UNIV S CAROLINA,DEPT PHARMACEUT SCI CHARLESTON SC 29425
Titolo Testata:
Blood
fascicolo: 11, volume: 92, anno: 1998,
pagine: 4279 - 4286
SICI:
0006-4971(1998)92:11<4279:DFTGCF>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE MYELOBLASTIC-LEUKEMIA; GM-CSF RECEPTOR; PROGENITOR CELLS; CYTOPLASMIC DOMAIN; HEMATOPOIETIC STEM; BONE-MARROW; TUMOR-CELLS; EXPRESSION; GROWTH; PROTEIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
37
Recensione:
Indirizzi per estratti:
Citazione:
A.E. Frankel et al., "DIPHTHERIA-TOXIN FUSED TO GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IS TOXIC TO BLASTS FROM PATIENTS WITH JUVENILE MYELOMONOCYTIC LEUKEMIA AND CHRONIC MYELOMONOCYTIC LEUKEMIA", Blood, 92(11), 1998, pp. 4279-4286

Abstract

We have previously demonstrated that human granulocyte-macrophage colony-stimulating factor fused to a truncated diphtheria toxin (DT388-GM-CSF) is toxic to patient acute myeloid leukemia progenitors bearing the GM-CSF receptor, but not normal marrow progenitors. We now report that exposure of mononuclear cells from five of seven (71%) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chronic myelomonocytic leukemia (CMML) patients to 10(-9) mol/L DT388-GM-CSF for 48 hours in culture reduces the number of cells capable of forming colonies in semisolid medium (colony-forming units-leukemia) 10-fold to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid progenitors (colony-forming unit-granulocyte-macrophage) from six different donors treated and assayed under identical conditions were consistently insensitive to the same fusion toxin even when treated as highly purified CD34(+) cells. The leukemic progenitors from the two otherJMML patients showed intermediate sensitivity to DT388-GM-CSF and theleukemic progenitors from eight of the 20 (40%) CMML patients were not different from normal progenitors. Parallel measurements of the number and affinity of GM-CSF receptors on cells from the same samples showed no consistent differences between JMML, CMML, and normal light density or CD34+ bone marrow cells. The increased sensitivity of leukemicprogenitors from all JMML progenitors and some CMML patients to the fusion toxin is therefore not likely to be explained by an increased density of GM-CSF receptors on these cells. We also examined the DT388-GM-CSF sensitivity of two murine cell lines transfected with cDNAs encoding varying portions of the human GM-CSF receptor or and/or beta chains. These studies showed that high-affinity ligand binding was sufficient for DT388-GM-CSF-induced toxicity, as this could occur even in theabsence of functional signal transduction and that the background of the host cell had a major influence on the degree to which this decreased the toxicity of DT388-GM-CSF. The selective sensitivity to DT388-GM-CSF of leukemic progenitors from a majority of JMML and CMML patients suggests that this agent could have therapeutic potential for some patients with these diseases; (C) 1998 by The American Society of Hematology.

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Documento generato il 27/01/20 alle ore 01:31:30