title: Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response.
abstract: Fludarabine, the current standard treatment for B-cell chronic lymphocytic leukemia (CLL), can induce apoptosis in CLL cells in vitro, and a number of molecular mechanisms contribute to its cytotoxicity. Using gene expression profiling, we investigated the molecular consequences of fludarabine treatment of patients with CLL in vivo. In 7 patients with CLL, a consistent gene expression signature of in vivo fludarabine exposure was identified. Many of the fludarabine signature genes were known p53 target genes and genes involved in DNA repair. In vitro treatment of CLL cells with fludarabine induced the same set of genes as observed in vivo, and many of these genes were also induced by in vitro exposure of CLL cells to ionizing radiation. Using isogenic p53 wild-type and null lymphoblastoid cell lines, we confirmed that many of the fludarabine signature genes were also p53 target genes. Because in vivo treatment with fludarabine induces a p53-dependent gene expression response, fludarabine treatment has the potential to select p53-mutant CLL cells, which are more drug resistant and associated with an aggressive clinical course. These considerations suggest that fludarabine treatment should be given in strict accordance to the current National Cancer Institute (NCI) guidelines that have established criteria of disease activity that warrant treatment.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute/NIH, Bldg 10, Rm 4N114, Bethesda, MD 20892, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chuang
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Diane C
authors.initials: DC
authors.lastname: Arthur
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Marti
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014740:Vidarabine / Q000008:administration & dosage* / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D014740:Vidarabine; C024352:fludarabine