title: Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy.
abstract: In addition to myelosuppression, anticancer drugs cause rapid and persistent depletion of lymphocytes, possibly by direct apoptosis induction in mature T and B cells. Induction of apoptosis regulators was analyzed in peripheral blood lymphocytes from pediatric patients undergoing first-cycle chemotherapy for solid tumors. In vivo chemotherapy induced a significant increase in lymphocyte apoptosis ex vivo. The activation of initiator caspase-8 and effector caspase-3 and the cleavage of caspase substrates was detected 12 to 48 hours after the onset of therapy. Caspase inhibition by Z-VAD-fmk did not reduce ex vivo lymphocyte apoptosis in all patients, indicating the additional involvement of caspase-independent cell death. No evidence for the involvement of activation-induced cell death was found in the acute phase of lymphocyte depletion as analyzed by activation marker expression and sensitivity for CD95 signaling. Lymphocyte apoptosis in vivo appeared to be predominantly mediated by the mitochondrial pathway because a marked decrease of mitochondrial membrane potential (DeltaPsi(M)) was detected after 24 to 72 hours of treatment, preceded by the increased expression of Bax. Interestingly, despite the use of DNA-damaging agents, p53 remained completely undetectable throughout treatment. In contrast, in vitro treatment with cytarabine and etoposide induced p53 protein, CD95 receptor expression, CD95 sensitivity, and CD95 receptor-ligand interaction in stimulated cycling lymphocytes, but no such induction was seen in resting cells. These data suggest that chemotherapy-induced lymphocyte depletion involves distinct mechanisms of apoptosis induction, such as direct mitochondrial and caspase-dependent pathways in resting cells and p53-dependent pathways in cycling lymphocytes.
authors.affiliation: Department of Pediatrics, University Children's Hospital, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Stahnke
authors.forename: S
authors.initials: S
authors.lastname: Fulda
authors.forename: C
authors.initials: C
authors.lastname: Friesen
authors.forename: G
authors.initials: G
authors.lastname: Strauss
authors.forename: K M
authors.initials: KM
authors.lastname: Debatin
mesh_terms: D000293:Adolescent; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007223:Infant; D007425:Intracellular Membranes / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; C494826:BAX protein, human; D015853:Cysteine Proteinase Inhibitors; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D020169:Caspases