thioguanine-anhydrous and Immunologic-Deficiency-Syndromes

A fibroblast cell strain, 46BR, derived from an immunodeficient patient is hypersensitive to the lethal effects of a wide range of DNA-damaging agents. It is also defective in strand-break rejoining after treatment with dimethyl sulfate and UV light. The present study shows that the cells have a defect in joining Okazaki-type fragments during DNA replication, supporting the interpretation that the basic defect is in ligation of DNA strands. The baseline level of sister chromatid exchange is slightly higher than in normal cells but it does not approach that of Bloom's syndrome or dyskeratosis congenita cells. Sensitivity to the induction of sister chromatid exchange and the hypersensitivity to the lethal effects of a set of DNA-damaging agents are correlated, implying that the basic defect influences both end points in a similar manner. No 6-thioguanine-resistant mutants could be induced by either gamma- or UV-irradiation in these cells, suggesting that error-prone repair pathways for damage induced by these agents may contain a common ligation step in human cells.

Topics: Cells, Cultured; DNA Ligases; DNA Repair; DNA Replication; Fibroblasts; Humans; Immunologic Deficiency Syndromes; Mutation; Polynucleotide Ligases; Sister Chromatid Exchange; Thioguanine

Topics: Ataxia Telangiectasia; Cells, Cultured; DNA Repair; Drug Resistance; Gamma Rays; Humans; Immunologic Deficiency Syndromes; Mutagens; Thioguanine; Ultraviolet Rays; Xeroderma Pigmentosum

Deficiency of erythrocytic and lymphocytic adenosine deaminase (ADA) occurs in some patients with severe combined immunodeficiency disease (SCID). SCID with ADA deficiency is inherited as an autosomal recessive trait. ADA is markedly reduced or undetectable in affected patients (homozygotes), and approximately one-half normal levels are found in individuals heterozygous for ADA deficiency. The metabolism of purine nucleosides was studied in erythrocytes from normal individuals, four ADA-deficiency patients, and two heterozygous individuals. ADA deficiency in intake erythrocytes was confirmed by a very sensitive ammonia-liberation technique. Erythrocytic ADA activity in three heterozygous individuals (0.07,0.08, and 0.14 mumolar units/ml of packed cells) was between that of the four normal controls (0.20-0.37 mumol/ml) and the ADA-deficient patients (no activity). In vitro, adenosine was incorporated principally into IMP in the heterozygous and normal individuals but into the adenosine nucleotides in the ADa-deficient patients. Coformycin (3-beta-D-ribofuranosyl-6,7,8-trihydroimidazo[4,5-4] [1,3] diazepin-8 (R)-ol), a potent inhibitor of ADA, made possible incorporation of adenosine nucleotides in the ADA-deficient patients...

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Adenosine Diphosphate; Adenosine Triphosphate; Azepines; Child, Preschool; Erythrocytes; Female; Formycins; Glycolysis; Guanosine; Humans; Immunologic Deficiency Syndromes; Infant; Inosine Monophosphate; Inosine Nucleotides; Male; Nucleoside Deaminases; Purine Nucleosides; Ribonucleosides; Thioguanine

A 19-yr-old boy has been in continuous complete remission from acute myelogenous leukemia for 3 yr after allogeneic bone marrow transplantation prepared with combination chemotherapy. During the first year post-transplant, however, the patient developed near-fatal graft-versus-host reaction followed by 11 severe viral and bacterial infections. Immune evaluation during this period revealed multiple defects which were not present prior to transplantation, nor present in the transplant donor: diminution of lymphoid tissue, decline of all immunoglobulin subtypes, deletion of secretory immunoglobulin, disappearance of isohemagglutinins, loss of antibody to diptheria and tetanus toxoids, cessation of cutaneous hypersensitivity to mumps antigen, and inhibition of serum opsonizing activity. The patient was also unable to develop normal humoral or cellular reactivity to brucella antigen, keyhole limpet hemocyanin, or dinitrochlorobenzene. This patient's course illustrates the severity and chronicity of immunoincompetence associated with allogeneic marrow grafting, the importance of early detection and rigorous treatment of infectious disease in these patients, and the need for improved immunologic reconstitution in human marrow transplantation. It also indicates that complete recovery from the immune defects is possible, and that long-term remission from acute myelogenous leukemia can be achieved with allogeneic marrow transplantation.

Topics: ABO Blood-Group System; Adolescent; Adult; Anti-Bacterial Agents; Antilymphocyte Serum; B-Lymphocytes; Bacterial Infections; Blood Group Incompatibility; Bone Marrow Cells; Bone Marrow Transplantation; Candidiasis; Cyclophosphamide; Cytarabine; Graft vs Host Reaction; Histocompatibility Antigens; Humans; Immunity, Maternally-Acquired; Immunologic Deficiency Syndromes; Leukemia, Myeloid, Acute; Male; Nitrosourea Compounds; Opsonin Proteins; T-Lymphocytes; Thioguanine; Transplantation, Homologous; Virus Diseases

Topics: Antibodies, Neoplasm; Antibody Formation; Antigen-Antibody Complex; Antigens, Neoplasm; BCG Vaccine; Cell Transformation, Neoplastic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Immunologic Deficiency Syndromes; Immunotherapy; Leukemia, Myeloid, Acute; Remission, Spontaneous; Thioguanine

Topics: Adult; Aged; Antibodies; Antigens; Cyclophosphamide; Cytarabine; Female; Hemocyanins; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Lectins; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocyte Activation; Lymphocytes; Male; Mercaptopurine; Methotrexate; Prednisone; Prognosis; Remission, Spontaneous; Skin Tests; Thioguanine; Vincristine