Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells

In vitro/in vivo correlations

D. Gottardi, A. M. De Leo, A. Alfarano, A. Stacchini, P. Circosta, M. G. Gregoretti, L. Bergui, M. Aragno, F. Caligaris-Cappio

Research output: Contribution to journalArticle

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Abstract

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 MR. The in vivo outcome after treatment with three to six courses of P-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.

Original languageEnglish
Pages (from-to)147-157
Number of pages11
JournalBritish Journal of Haematology
Volume99
Issue number1
Publication statusPublished - 1997

Fingerprint

bcl-2 Genes
Aptitude
B-Lymphocytes
Down-Regulation
Apoptosis
Mantle-Cell Lymphoma
Methylprednisolone
B-Cell Chronic Lymphocytic Leukemia
In Vitro Techniques
fludarabine
Vidarabine
Cell Death
Lymphocytes

Keywords

  • Apoptosis
  • B-chronic lymphocytic leukaemia
  • Bcl- 2
  • CD5 B cells
  • Fludarabine

ASJC Scopus subject areas

  • Hematology

Cite this

Gottardi, D., De Leo, A. M., Alfarano, A., Stacchini, A., Circosta, P., Gregoretti, M. G., ... Caligaris-Cappio, F. (1997). Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells: In vitro/in vivo correlations. British Journal of Haematology, 99(1), 147-157.

Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells : In vitro/in vivo correlations. / Gottardi, D.; De Leo, A. M.; Alfarano, A.; Stacchini, A.; Circosta, P.; Gregoretti, M. G.; Bergui, L.; Aragno, M.; Caligaris-Cappio, F.

In: British Journal of Haematology, Vol. 99, No. 1, 1997, p. 147-157.

Research output: Contribution to journalArticle

Gottardi, D, De Leo, AM, Alfarano, A, Stacchini, A, Circosta, P, Gregoretti, MG, Bergui, L, Aragno, M & Caligaris-Cappio, F 1997, 'Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells: In vitro/in vivo correlations', British Journal of Haematology, vol. 99, no. 1, pp. 147-157.
Gottardi D, De Leo AM, Alfarano A, Stacchini A, Circosta P, Gregoretti MG et al. Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells: In vitro/in vivo correlations. British Journal of Haematology. 1997;99(1):147-157.
Gottardi, D. ; De Leo, A. M. ; Alfarano, A. ; Stacchini, A. ; Circosta, P. ; Gregoretti, M. G. ; Bergui, L. ; Aragno, M. ; Caligaris-Cappio, F. / Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells : In vitro/in vivo correlations. In: British Journal of Haematology. 1997 ; Vol. 99, No. 1. pp. 147-157.
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abstract = "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 MR. The in vivo outcome after treatment with three to six courses of P-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.",
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