Document Detail


Glucocorticoids induce G1 arrest of lymphoblastic cells through retinoblastoma protein Rb1 dephosphorylation in childhood acute lymphoblastic leukemia in vivo.
MedLine Citation:
PMID:  15034294     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Childhood Acute Lymphoblastic Leukemia (ALL) represents approximately 40% of pediatric cancers, but molecular mechanisms involved in the therapeutic resistance of ALL are still unclear. The disregulation of cell cycle could be a mechanism of progression of leukemic blasts and glucocorticoids (GCs), the main pharmacological agent in the treatment of ALL, could affect cell cycle distribution. In our study we have evaluated cell cycle distribution and the expression of several molecules involved in cell cycle regulation in blasts collected from 32 patients with ALL before and 48 h after treatment with GCs. A significant increase of the percentage of ALL blasts in G(0)/G(1) phase was recorded after treatment with GCs in 22 (69%) out of 32 patients and 18 of these patients were also good responders to GC therapy. In these patients an increase of the expression of at least one of the 4 evaluated CDKIs (p15, p16, p21 and p27) was found in 29 out of 32 patients (90.6%) without any change in CDK2 and 4 expression. All patients expressed detectable levels of Rb-1 phosphorylation at the diagnosis. Twenty (63%) patients showed a decrease, while two patients showed an increase of p110 Rb-1 phosphorylation and no changes were detected in the remaining 10 patients after GC therapy. The univariate analysis showed that the reduction of pRb-1 phosphorylation was significantly higher in B-cell lineage patients and in good responders. In conclusion, this is the first report that evaluate the Rb-1 function as predictor of response in childhood ALL and our data suggest that its hypophosphorylation and, consequently, reduced activity correlates with a statistical significance with the responsiveness to GC therapy. These results suggest that Rb-1 can be a useful molecular target for the therapy of this subset of patients.
Authors:
Raffaele Addeo; Fiorina Casale; Michele Caraglia; Velia D'Angelo; Stefania Crisci; Alberto Abbruzzese; Maria Teresa Di Tullio; Paolo Indolfi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-05-09
Journal Detail:
Title:  Cancer biology & therapy     Volume:  3     ISSN:  1538-4047     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-08-26     Completed Date:  2005-05-17     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  470-6     Citation Subset:  IM    
Affiliation:
Pediatric Oncology Service, Pediatric Department, II University of Naples, Napoli, Italy.
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MeSH Terms
Descriptor/Qualifier:
Blast Crisis
Cell Cycle Proteins / metabolism
Child
Cyclins / metabolism
Female
G1 Phase / drug effects*
Glucocorticoids / therapeutic use*
Humans
Male
Phosphorylation
Precursor Cell Lymphoblastic Leukemia-Lymphoma / diagnosis,  drug therapy*,  metabolism
Prednisone / therapeutic use*
Retinoblastoma Protein / metabolism*
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Cyclins; 0/Glucocorticoids; 0/Retinoblastoma Protein; 53-03-2/Prednisone

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