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M94A3199.TXT
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1994-10-25
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Document 3199
DOCN M94A3199
TI Mechanisms of 2'3'-dideoxycytidine-induced murine thymic lymphoma.
DT 9412
AU Irons RD; Le AT; Stillman WS; University of Colorado Health Sciences
Center Molecular; Toxicology & Environmental Health Sciences Program,
Denver 80262.
SO Int Conf AIDS. 1994 Aug 7-12;10(1):130 (abstract no. PA0138). Unique
Identifier : AIDSLINE ICA10/94369376
AB The nucleoside analoque, 2',3'-dideoxycytidine (ddC), is a potent
inhibitor of human immunodeficiency virus reverse transcriptase that
exhibits a different toxicity profile than zidovudine (AZT). AIDS
patients treated with ddC have experienced clinical improvement without
significant hematologic toxicity. However, it has recently been reported
that repeated administration of ddC (1000 mg/kg/day) for 13 weeks
results in an increased incidence of thymic lymphoma (TL) in B6C3F1
mice. Experiments are underway in our laboratory to elucidate the
mechanism of ddC induced TL. Previous studies have revealed a common
link between chemically induced and genetically associated models of
mouse TL that are due to a common defect in a subpopulation of primitive
hematopoietic progenitor cells (HPC). These studies reveal a
subpopulation of c-kit-dependent IL-3 responsive HPC that are suppressed
by the murine leukemogen, 1.3-butadiene, and are absent in mice bearing
SI/SId and W/WV mutations. Initial experiments reveal that
administration of ddC to C57BL/6 mice in vivo (1-2 gm/kg) or
pretreatment of bone marrow cells for 1 hr in vitro (1 mM) results in a
selective suppression of a subpopulation of IL-3 responsive HPC similar
to that previously described in other models of murine TL. Studies are
in progress to further characterize and define ddC-induced suppression
of cytokine response in C57BL/6, CD-1 and B6C3F1 mice. Results of these
studies will be compared to those obtained using human bone marrow cells
in order to ascertain the relevance of the mouse as a predictive model
of ddC hematotoxicity in humans.
DE Acquired Immunodeficiency Syndrome/DRUG THERAPY Animal Bone
Marrow/DRUG EFFECTS/PATHOLOGY Butadienes/PHARMACOLOGY
Carcinogens/*TOXICITY Comparative Study Hematopoietic Stem
Cells/CYTOLOGY/DRUG EFFECTS/METABOLISM Human
Interleukin-3/PHARMACOLOGY Lymphoma/*CHEMICALLY INDUCED Mice Mice,
Inbred C57BL Mice, Inbred Strains Mice, Mutant Strains Proto-Oncogene
Proteins/METABOLISM Receptor Protein-Tyrosine Kinase/METABOLISM
Receptors, Colony-Stimulating Factor/METABOLISM Support, Non-U.S. Gov't
Thymus Neoplasms/*CHEMICALLY INDUCED Zalcitabine/*TOXICITY/THERAPEUTIC
USE MEETING ABSTRACT
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).