Inhibitory effect of azidothymidine, 2'-3'-dideoxyadenosine, and 2'-3'-dideoxycytidine on in vitro growth of hematopoietic progenitor cells from normal persons and from patients with AIDS. 1989

A Ganser, and J Greher, and B Völkers, and S Staszewski, and D Hoelzer
Department of Hematology, University of Frankfurt, FRG.

Therapy of patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) with azidothymidine (AZT) and 2'-3'-dideoxycytidine (ddC) is complicated by severe anemia, neutropenia, and thrombocytopenia, the cause of which is unknown. We therefore tested the effect of AZT, ddC, and an additional 2'-3'-dideoxynucleoside analogue, 2'-3'-dideoxyadenosine (ddA), on the hematopoietic progenitor cells derived from the bone marrow of normal persons and patients with AIDS/ARC. All three substances dose-dependently inhibited the in vitro colony formation of the pluripotent (CFU-GEMM), as well as the erythroid (BFU-E) and granulocyte-macrophage progenitor cells (CFU-GM). The 50% inhibition of normal progenitors by AZT occurred at 0.13 microM for CFU-GEMM, 0.32 microM for BFU-E, and 1.9 microM for CFU-GM, by ddA at 15 microM for CFU-GEMM, 40 microM for BFU-E, and 140 microM for CFU-GM. ddC was the most toxic agent and already inhibited 71% +/- 16% (mean +/- standard error of the mean [SEM]) of CFU-GEMM and 52% +/- 22% of BFU-E at 0.1 microM, whereas the 50% inhibition of CFU-GM was reached at 0.3 microM. Hematotoxicity occurred at concentrations lower than necessary to inhibit the human immunodeficiency virus (HIV), except for ddA, which is 100 times less toxic than AZT whereas its antiviral effect is only 10 times less. The inhibition of progenitor cells from AIDS patients by the 2'-3'-dideoxynucleosides was comparable to normal progenitors, except for a higher sensitivity of AIDS-derived CFU-GEMM and BFU-E to AZT.

UI MeSH Term Description Entries
D001853 Bone Marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Marrow,Red Marrow,Yellow Marrow,Marrow, Bone,Marrow, Red,Marrow, Yellow
D003114 Colony-Forming Units Assay A cytologic technique for measuring the functional capacity of stem cells by assaying their activity. Clonogenic Cell Assay,Stem Cell Assay,Clonogenic Cell Assays,Colony Forming Units Assays,Colony-Forming Units Assays,Stem Cell Assays,Assay, Clonogenic Cell,Assay, Colony-Forming Units,Assay, Stem Cell,Assays, Clonogenic Cell,Assays, Colony-Forming Units,Assays, Stem Cell,Colony Forming Units Assay
D003853 Deoxyribonucleosides A purine or pyrimidine base bonded to DEOXYRIBOSE.
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006131 Growth Inhibitors Endogenous or exogenous substances which inhibit the normal growth of human and animal cells or micro-organisms, as distinguished from those affecting plant growth ( Cell Growth Inhibitor,Cell Growth Inhibitors,Growth Inhibitor,Growth Inhibitor, Cell,Growth Inhibitors, Cell,Inhibitor, Cell Growth,Inhibitor, Growth,Inhibitors, Cell Growth,Inhibitors, Growth
D006410 Hematopoiesis The development and formation of various types of BLOOD CELLS. Hematopoiesis can take place in the BONE MARROW (medullary) or outside the bone marrow (HEMATOPOIESIS, EXTRAMEDULLARY). Hematopoiesis, Medullary,Haematopoiesis,Medullary Hematopoiesis
D006412 Hematopoietic Stem Cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Colony-Forming Units, Hematopoietic,Progenitor Cells, Hematopoietic,Stem Cells, Hematopoietic,Hematopoietic Progenitor Cells,Cell, Hematopoietic Progenitor,Cell, Hematopoietic Stem,Cells, Hematopoietic Progenitor,Cells, Hematopoietic Stem,Colony Forming Units, Hematopoietic,Colony-Forming Unit, Hematopoietic,Hematopoietic Colony-Forming Unit,Hematopoietic Colony-Forming Units,Hematopoietic Progenitor Cell,Hematopoietic Stem Cell,Progenitor Cell, Hematopoietic,Stem Cell, Hematopoietic,Unit, Hematopoietic Colony-Forming,Units, Hematopoietic Colony-Forming
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000163 Acquired Immunodeficiency Syndrome An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive T-lymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. AIDS,Immunodeficiency Syndrome, Acquired,Immunologic Deficiency Syndrome, Acquired,Acquired Immune Deficiency Syndrome,Acquired Immuno-Deficiency Syndrome,Acquired Immuno Deficiency Syndrome,Acquired Immuno-Deficiency Syndromes,Acquired Immunodeficiency Syndromes,Immuno-Deficiency Syndrome, Acquired,Immuno-Deficiency Syndromes, Acquired,Immunodeficiency Syndromes, Acquired,Syndrome, Acquired Immuno-Deficiency,Syndrome, Acquired Immunodeficiency,Syndromes, Acquired Immuno-Deficiency,Syndromes, Acquired Immunodeficiency
D000386 AIDS-Related Complex A prodromal phase of infection with the human immunodeficiency virus (HIV). Laboratory criteria separating AIDS-related complex (ARC) from AIDS include elevated or hyperactive B-cell humoral immune responses, compared to depressed or normal antibody reactivity in AIDS; follicular or mixed hyperplasia in ARC lymph nodes, leading to lymphocyte degeneration and depletion more typical of AIDS; evolving succession of histopathological lesions such as localization of Kaposi's sarcoma, signaling the transition to the full-blown AIDS. ARC,Lymphadenopathy Syndrome,AIDS Related Complex,Complex, AIDS-Related,Lymphadenopathy Syndromes,Syndrome, Lymphadenopathy,Syndromes, Lymphadenopathy

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