title: Diversity of the apoptotic response to chemotherapy in childhood leukemia.
abstract: Apoptosis is the primary mechanism through which most chemotherapeutic agents induce tumor cell death. The purpose of this study was to determine the extent to which blasts from children with leukemia undergo a uniform apoptotic death pathway in vivo. The expression of pro- and anti-apoptotic proteins p53, p21, MDM-2, BCL-2, BCL-X(L), BCL-X(S), and BAX, and caspase-3 activity was determined in circulating blasts collected from the peripheral blood of children with leukemia prior to, and at serial time points following chemotherapy. Culturing blasts ex vivo for 12 h assessed spontaneous apoptosis and the increment induced by chemotherapy. Baseline apoptosis varied between 3% and 29%. Twenty-four hours following chemotherapy the increase in the percentage of cells undergoing apoptosis ranged from <1% to 38%. Eleven of 20 patients who received initial treatment with a p53-dependent drug showed an increase in p53 expression. In these patients, the levels of p53 target genes were also increased. A uniform pattern of BCL-2 family protein expression was not observed and only a minority of samples showed a change that would favor apoptosis. We conclude that that the initial apoptotic response to chemotherapy in children with leukemia is variable involving both p53-dependent and p53-independent pathways.
authors.affiliation: Center for Children at the Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: E
authors.initials: E
authors.lastname: Raetz
authors.forename: P J
authors.initials: PJ
authors.lastname: Moos
authors.forename: S L
authors.initials: SL
authors.lastname: Perkins
authors.forename: C S
authors.initials: CS
authors.lastname: Bruggers
authors.forename: F
authors.initials: F
authors.lastname: Smith
authors.forename: W L
authors.initials: WL
authors.lastname: Carroll
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D019254:Genes, bcl-2; D016158:Genes, p53; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage / Q000494:pharmacology; D007223:Infant; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D013866:Thioguanine / Q000008:administration & dosage / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494826:BAX protein, human; C494811:BCL2L1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D014750:Vincristine; D005047:Etoposide; D003907:Dexamethasone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013866:Thioguanine; D011241:Prednisone; D015255:Idarubicin; D003630:Daunorubicin