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Fludarabine ability to down‐regulate Bcl‐2 gene product in CD5 + leukaemic B cells: in vitro / in vivo correlations
Author(s) -
Gottardi D.,
De Leo A. M.,
Alfarano A.,
Stacchini A.,
Circosta P.,
Gregoretti M. G.,
Bergui L.,
Aragno M.,
CaligarisCappio F.
Publication year - 1997
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1997.3353152.x
Subject(s) - fludarabine , in vivo , in vitro , cd5 , gene , cancer research , product (mathematics) , gene product , microbiology and biotechnology , biology , genetics , medicine , chemistry , gene expression , cyclophosphamide , chemotherapy , flow cytometry , geometry , mathematics
CD5 + B‐chronic lymphocytic leukaemia (B‐CLL) and mantle cell lymphoma (MCL) in leukaemic phase are characterized by defects in cell death induction that primarily involves the Bcl‐2 family of genes. Fludarabine (9‐β‐ D ‐arabinofuranosyl‐2‐fluoradenine, F‐ara‐A) is a potent inducer of apoptosis in CLL cells. This study aimed to determine whether F‐ara‐A‐induced apoptosis might be related to Bcl‐2 modifications and to evaluate in vitro/in vivo correlations. Peripheral blood lymphocytes from eight B‐CLL and four leukaemic MCL were cultured in the presence of different concentrations of F‐ara‐A ±methylprednisolone (MP). F‐ara‐A down‐regulated the expression of Bcl‐2 in 5/12 cases. mRNA down‐regulation was maximal at 48 h; protein down‐regulation was prominent after 48 h. Both events were dose‐dependent. The amount of apoptosis was significantly higher in the samples treated with F‐ara‐A than in those exposed to MP alone. In the seven remaining cases, no Bcl‐2 down‐regulation was observed after exposure to F‐ara‐A and the degree of F‐ara‐A‐induced apoptosis overlapped that induced by MP. The in vivo outcome after treatment with three to six courses of F‐ara‐A was evaluable in 10 patients: 4/5 cases, whose cells had shown in vitro Bcl‐2 down‐regulation and prominent apoptosis after exposure to F‐ara‐A, had a complete response (CR) and a partial response (PR) was observed in the remaining patient. Of the five patients whose cells had shown no in vitro Bcl‐2 modulation after exposure to F‐ara‐A, two had a PR, but the other three did not show any in vivo clinical response.