Adhesion molecules and Differentiation Syndrome: phenotypic and functional analysis of the effect of ATRA, As2O3, phenylbutyrate, and G-CSF in acute promyelocytic leukemia.
OBJECTIVE
Differentiation Syndrome (DS) is a treatment complication which can occur in patients treated with acute promyelocytic leukemia (APL) with all transretinoic acid (ATRA) or As(2)O(3), and is characterized by enhanced leukocyte transmigration. As(2)O(3), Phenylbutyrate (PB) and G-CSF are known to potentiate ATRA effects. Our aim was to analyze the changes in expression and function of adhesion molecules induced by ATRA, As(2)O(3), G-CSF and PB, and their association.


METHODS
APL blasts and NB4 cells were treated with ATRA, As(2)O(3), PB, G-CSF or their association and the expression of adhesion molecules was determined by flow cytometry. Cell adhesion was evaluated in vitro using Matrigel and for the in vivo analysis, Balb-c mice were injected with NB4 cells pre-treated with ATRA, As(2)O(3), ATRA+G-CSF or ATRA+As(2)O(3). In addition, CD54 and CD18 knock-out mice were injected with NB4 cells and concomitantly treated with ATRA. In both models, the MPO activity in the lungs was determined 6 hours after the injection of the cells.


RESULTS
In NB4 and APL blasts, ATRA and As(2)O(3) increased CD54 expression, but no synergism was detected. CD11b and CD18 were also up-regulated by ATRA in primary cells. PB and G-CSF had no effect, but the latter potentiated ATRA-induced CD18 up-regulation. These changes were accompanied by increased adhesion to Matrigel and to lung microvasculature, and reversed by anti-CD54, anti-CD18 antibodies. In CD54 and CD18 knock-out mice the ATRA effect was canceled.


CONCLUSIONS
The use of As(2)O(3), PB and G-CSF in association with ATRA should not aggravate DS in APL.
Hematology Division and Center for Cell Based Therapy, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Brazil.
Gil
G
Cunha De Santis
Mirela de Barros
MB
Tamarozzi
Romualdo Barroso
RB
Sousa
Susana Elisa
SE
Moreno
Daniela
D
Secco
Aglair Bergamo
AB
Garcia
Ana Sílvia Gouveia
AS
Lima
Lúcia Helena
LH
Faccioli
Roberto Passetto
RP
Falcão
Fernando Queirós
FQ
Cunha
Eduardo Magalhães
EM
Rego
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000819:agonists / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000819:agonists / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000819:agonists / Q000494:pharmacology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010087:Oxides / Q000819:agonists / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000819:agonists / Q000494:pharmacology*; D013577:Syndrome; D014212:Tretinoin / Q000819:agonists / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000970:Antineoplastic Agents; D001152:Arsenicals; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D010087:Oxides; D010654:Phenylbutyrates; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D000077237:Arsenic Trioxide