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Blood, 15 November 2001, Vol. 98, No. 10, pp. 3066-3073
NEOPLASIA
Activation of apoptosis pathways in peripheral blood
lymphocytes by in vivo chemotherapy
Karsten Stahnke,
Simone Fulda,
Claudia Friesen,
Gudrun Strauß, and
Klaus-Michael Debatin
From the Department of Pediatrics, University
Children's Hospital, Ulm; and the Division of Molecular Oncology,
German Cancer Research Center, Heidelberg, Germany.
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
(  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.
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The common pathways, but different outcomes, of apoptosis induced by extracorporeal photopheresis and in vivo chemotherapy may reinforce the important immunomodulatory effect of monocytes
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Blood 2002 99: 3071-3072.
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