mercaptopurine and Necrosis

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Enterocolitis, Pseudomembranous; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Necrosis; Recovery of Function; Remission Induction; Tretinoin; Vancomycin

Arsenic trioxide (As2O3) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 x 10(3)/microl increased to 134 x 10(3)/microl following the administration of As2O3. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 x 10(3)/microl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (Cpmax) and a half-life time (t1/2) of 6.9 microm and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As2O3 therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow; Bone Marrow Diseases; Fever; Humans; Hydroxyurea; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Necrosis; Oxides; Pancytopenia; Remission Induction

To study effects of pharmacologic concentrations of azathioprine and 6-mercaptopurine (6-MP) on rat hepatocytes.. Hepatocytes cultured on matrigel were incubated with azathioprine or 6-MP; effects of putative protective agents were studied. Viability (LDH leakage), reduced (GSH) and oxidized glutathione (GSSG), mitochondrial (mt) GSH, ATP and ultrastructural changes were determined.. Azathioprine and 6-MP (0.5-5 micromol/l) reduced viability 5-34% at day 1 and 42-92% by day 4. Allopurinol (20 microM) (xanthine oxidase inhibitor) and 2 mM Trolox (vitamin E analog) together provided near complete protection. During culture with azathioprine, GSSG increased before cell death and there was a disproportionate reduction of mtGSH and ATP, together with ultrastructural abnormalities in mitochondria. All changes were prevented by allopurinol and trolox. Discontinuation of 1 micromol/l azathioprine restored ATP levels and arrested cell injury, while culture in glucose-enriched media augmented ATP levels and ameliorated cell death.. Clinically relevant concentrations of azathioprine and 6-MP are toxic to rat hepatocyte cultures by a mechanism that involves oxidative stress, mitochondrial injury and ATP depletion. This can lead to irreversible de-energization and cell death by oncosis (necrosis).

Topics: Adenosine Triphosphate; Allopurinol; Animals; Antioxidants; Azathioprine; Cell Differentiation; Cell Survival; Cells, Cultured; Chromans; Enzyme Inhibitors; Glutathione; Glutathione Disulfide; Hepatocytes; Male; Mercaptopurine; Microscopy, Electron; Mitochondria, Liver; Necrosis; Oxidative Stress; Rats; Rats, Wistar; Time Factors; Xanthine Oxidase

The fungus Fusarium moniliforme causes fusariosis, which can be invasive and fatal in immunocompromised patients. We report a case of oral Fusarium infection in a granulocytopenic patient with acute myelogenous leukemia who developed necrotic ulceration of the gingiva, extending to the alveolar bone, but was otherwise free of any active systemic lesions. Fusarium moniliforme was identified, by histopathology and culture, to be present in the lesion and was deduced to be the causative organism for this invasive oral infection.

Topics: Acute Kidney Injury; Aged; Agranulocytosis; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Epirubicin; Etoposide; Fatal Outcome; Fusarium; Gingival Diseases; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Maxillary Diseases; Mercaptopurine; Mycoses; Necrosis; Prednisolone; Ulcer; Vindesine

Isoproterenol produces myocardial necrosis in rats. To investigate the possible role of oxygen free radicals generated by xanthine oxidase and neutrophils, we examined the effects of the xanthine oxidase inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG) combined and allopurinol, or of irradiation (to induce leukopenia) on isoproterenol-induced myocardial necrosis (ISOMN). The incidence and severity of ISOMN was significantly reduced by 6MP + 6TG but not by the specific inhibitor of xanthine oxidase, allopurinol, indicating that the protective effects of 6MP + 6TG may be due to its free radical scavenging activity rather than its xanthine oxidase inhibitory activity. Irradiation provided complete protection against ISOMN in all rats. Marked leukopenia or other radiation-induced protective factors could play a role in the mechanism of the protection.

Topics: Allopurinol; Animals; Heart Diseases; Isoproterenol; Leukocytes; Leukopenia; Male; Mercaptopurine; Myocardium; Necrosis; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Thioguanine

The prenatal cortex development after the application of 6-Mercaptopurine (6-MP) was studied in the rat embryo. 24 h after application of a single dose of 6-MP on day 12, 13, 14 or 15 of gestation first cell lesions occured in the form of necroses. 48 h after injection of the drug these necroses were most pronounced. Their extent and distribution pattern was, however, dependent on the developmental stage. In the early developmental phase, on days 12 and 13, massive necroses could be observed in the intermediate zone. At later stages of development (drug application on day 14 or 15) damaged cells could occasionally also be found scattered over the whole ventricular wall. The late toxic response to 6-MP treatment suggests that, after incorporation of metabolites of the agent into DNA during the S-phase, at least one additional S-phase is completed before the disturbance created in a cell is sufficient to cause necrosis. The necrosis may be a result of an action of 6-MP directly on DNA or via an affect on transcription. The different extent of the lesion during the various developmental phases suggests different growth dynamics of the cortex.

Topics: Animals; Cerebral Cortex; Female; Gestational Age; Male; Mercaptopurine; Necrosis; Rats

During a 7 1/2-yr period we monitored a chromosomally aberrant cell line in a woman with acute granulocytic leukemia (AGL) whose disease followed a rather unusual course. Her initial remission induced with 6-mercaptopurine (6-MP) and prednisone was maintained for 52 mo with biweekly doses of methotrexate (MTX) given orally. Because signs of liver dysfunction occurred, maintenance therapy was stopped. After 15 mo without chemotherapy, she suffered her first relapse (5 yr 7 mo after the initial diagnosis). A second remission, again induced with 6-MP and prednisone, was maintained for 1 yr, after which a second relapse occurred. Another remission lasting for only 4 mo was followed by a relapse of the leukemic process which led to her death. Cytogenetic studies of marrow cells and peripheral blood at the time of her initial diagnosis showed abnormal stem lines with characteristic chromosome markers. A small percentage of malignant cells bearing these markers persisted in her marrow during the years of her prolonged remission. At the time of her first relapse, 75% of her marrow cells had the marker karyotype, and at the time of her death (7 1/2 yr after the leukemia was diagnosed) all analyzable marrow metaphases had the characteristic chromosome changes.

Topics: Adolescent; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Chromosome Aberrations; Fatty Liver; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Liver; Mercaptopurine; Mitosis; Necrosis; Prednisone; Remission, Spontaneous

On day 12 of pregnancy Wistar rats were each given a single ip injection of 5, 8, 16, 25, or 50 mg/kg 6-mercaptopurine. The embryos were removed 1, 2, 3, 5, 6, 10, 24, 48, or 72 h after injection or on day 20 and studied by light and electron microscopy. After 25 or 50 mg/kg all embryos showed no mineralization in the lower extremities. By electron microscopy condensation, shrinking, and fragmentation of cells in the limb bud blastema could be seen after 5 h. The fragments were phagocytosed and broken down by neighboring cells or remained in the extracellular space. After 25 or 50 mg/kg the damage was so extensive that the number of undamaged cells and of cells transforming into phagocytes was not sufficient to remove the debris or to compensate for the defect by mitotic activity. Epithelial cells, nerves, and blood vessels, show no morphological signs of damage. The "critical period" was the time cartilage just starts developing, i.e., when the blastema begins to differentiate.

Topics: Animals; Antineoplastic Agents; Epithelium; Extremities; Female; Mercaptopurine; Mice; Microscopy, Electron; Necrosis; Phagocytes; Phagocytosis; Pregnancy; Time Factors

Wistar rats were administered single doses of 16 or 50 mg/kg 6-mercaptopurine (6-MP) on day 12 of pregnancy. Necrosis in the fetal forebrain and spinal cord was studied by light microscope 6, 12, 14, 48, 72, and 81 h and 8 days afterward. The extent of necrosis was dose dependent. The first necroses were seen after 24 h, regardless of location (brain, spinal cord) or dose; but the extent was greatest after 48 h. All necrotic cells had a typical appearance; they were ballooned and often fragmented, their nuclei were darkly colored and frequently pyknotic, and they were often karyorhexic. Necroses appeared almost exclusively at sites of beginning cellular differentiation, i.e., in the intermediate zone. In the spinal cord the ventricular zone was also necrotic and the alar plate (dorsal horn) always affected. Phagocytizing cells (macrophages) appeared in the spinal cord after 48 h and in the brain after 72 h. After 81 h all the necrotic material had been phagocytized, at which time there was a massive congestion of the extra- and intracerebral vessels. Hemorrhages appeared in defined localizations. Eight days after exposure to 16 mg/kg 6-MP fetuses no longer showed any visible deviations. Fetuses exposed to 50 mg/kg showed deviations in the cytoarchitecture of the neopallium: an extremely broadened ventricular zone, few cells in the intermediate zone, and extensive rarefaction cells in the cortical plate with no clear layer structure. In the spinal cord, cleft formations were especially noticeable in the dorsal-horn region. All fetuses showed a hydrocephalus externus after 50 mg/kg. The mechanism leading to necrosis is discussed.

Topics: Abnormalities, Drug-Induced; Animals; Brain; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Hydrocephalus; Intracranial Arteriovenous Malformations; Macrophages; Mercaptopurine; Necrosis; Phagocytosis; Pregnancy; Rats; Spinal Cord; Teratogens

Topics: Animals; Carbon Tetrachloride Poisoning; Disease Models, Animal; Hydrocortisone; Immunosuppressive Agents; Liver; Male; Mercaptopurine; Necrosis; Rabbits

Topics: Adult; Asparaginase; Breast Neoplasms; Cecal Diseases; Child; Cytarabine; Daunorubicin; Female; Fluorouracil; Humans; Intestinal Perforation; Leukemia; Male; Mercaptopurine; Methotrexate; Middle Aged; Necrosis; Prednisone; Thioguanine; Vincristine

Topics: Abnormalities, Drug-Induced; Animals; Cell Survival; Cyclophosphamide; Dactinomycin; Embryo, Mammalian; Embryonic and Fetal Development; Female; Fetus; Magnesium Deficiency; Mercaptopurine; Mice; Mice, Inbred Strains; Microscopy, Electron; Necrosis; Niacinamide; Pregnancy; Rats; Rats, Inbred Strains; Vincristine; Vitamin A

Topics: Abscess; Antineoplastic Agents; Histocytochemistry; Humans; Leukemia, Myeloid; Male; Mercaptopurine; Middle Aged; Necrosis; Prednisone; Shwartzman Phenomenon; Skin Manifestations

Topics: Adult; Female; Gonadotropins; Humans; Hydatidiform Mole; Hysterectomy; Mercaptopurine; Methotrexate; Middle Aged; Necrosis; Pregnancy; Trophoblasts

Topics: Animals; Antilymphocyte Serum; Cicatrix; Dogs; Electrodes, Implanted; Female; Fibroblasts; Heart; Humans; Immunosuppressive Agents; Inflammation; Male; Mercaptopurine; Myocardium; Necrosis; Pacemaker, Artificial; Prednisone; Rats; Tissue Survival

Topics: Animals; Antibiotics, Antineoplastic; Antibody Formation; Arthus Reaction; Cortisone; Depression, Chemical; Flavonoids; Hyperemia; Immune Sera; Male; Mercaptopurine; Necrosis; Oxytetracycline; Precipitins; Rabbits; Time Factors

Topics: Animals; Conjunctiva; Female; Inflammation; Male; Mercaptopurine; Necrosis; Rabbits; Transplantation Immunology; Transplantation, Homologous

Topics: Acute Disease; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Biliary Tract Diseases; Biopsy; Child; Child, Preschool; Cholestasis; Chronic Disease; Diagnosis, Differential; Female; Hepatitis; Hepatitis A; Humans; Infant; Infant, Newborn; Liver Cirrhosis; Liver Cirrhosis, Biliary; Male; Mercaptopurine; Middle Aged; Necrosis

Topics: Animals; Antibody Formation; Blood Chemical Analysis; Cortisone; Fibroma; Lagomorpha; Mercaptopurine; Necrosis; Oncogenic Viruses; Rabbits; Research; Skin Neoplasms; Tumor Virus Infections