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).