Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cure of childhood acute lymphoblastic leukemia (ALL) was a momentous achievement in the history of medicine. It demonstrated that widely disseminated cancers can be eradicated with cytotoxic drugs, and it illustrated the power of systematic laboratory studies and randomized clinical trials applied to a single disease. As ALL cure rates edge towards 80%, several key challenges are apparent. First, it will be important to devise more effective therapies for the high-risk patients who continue to relapse on contemporary protocols. Second, better methods of disease assessment and treatment are needed to avoid relapses that still occur in so-called low- and intermediate-risk groups. Third, the persistence of late adverse effects due to radiation and certain genotoxic agents, such as the anthracycline compounds and the epipodophyllotoxins, mandates the development of alternative therapies that are both safe and effective in children. The International Childhood ALL Workshop, held 3-4 December 1997, at St Jude Children's Research Hospital in Memphis, Tennessee, brought together leading experts in leukemia therapy to discuss progress in meeting these and other challenges, and to suggest directions for future studies. The participants, from 12 co-operative study groups and two individual centers, were welcomed by Dr A Nienhuis (St Jude Director), who provided the historical context for the workshop, and by Drs W Evans and C-H Pui, the meeting co-organizers.
Leukemia 1998 Aug
PMID:Meeting report: International Childhood ALL Workshop: Memphis, TN, 3-4 December 1997. 969 89

Histone deacetylases (HDACs) are a growing family of enzymes implicated in transcriptional regulation by affecting the acetylation state of core histones in the nucleus of cells. HDACs are known to have key roles in the regulation of cell proliferation [Brehm, Miska, McCance, Reid, Bannister and Kouzarides (1998) Nature (London) 391, 597-600], and aberrant recruitment of an HDAC complex has been shown to be a key step in the mechanism of cell transformation in acute promyelocytic leukaemia [Grignani, De Matteis, Nervi, Tomassoni, Gelmetti, Cioce, Fanelli, Ruthardt, Ferrara, Zamir et al. (1998) Nature (London) 391, 815-818; Lin, Nagy, Inoue, Shao, Miller and Evans (1998), Nature (London) 391, 811-814]. Here we present the complete nucleotide sequence of a cDNA clone, termed HDAC8, that encodes a protein product with similarity to the RPD3 class (I) of HDACs. The predicted 377-residue HDAC8 product contains a shorter C-terminal extension relative to other members of its class. After expression in two cell systems, immunopurified HDAC8 is shown to possess trichostatin A- and sodium butyrate-inhibitable HDAC activity on histone H4 peptide substrates as well as on core histones. Expression profiling reveals the expression of HDAC8 to various degrees in every tissue tested and also in several tumour lines. Mutation of two adjacent histidine residues within the predicted active site severely decreases activity, confirming these residues as important for HDAC8 enzyme activity. Finally, linkage analysis after radiation hybrid mapping has localized HDAC8 to chromosomal position Xq21.2-Xq21.3. These results confirm HDAC8 as a new member of the HDAC family.
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PMID:Cloning and characterization of a novel human histone deacetylase, HDAC8. 1092 44

Primary auto-immune neutropenia (AIN) is usually described in children. Secondary AIN occurs in collagen vascular diseases such as rheumatoid arthritis and (Felty's syndrome), Gougerot-Sjogren syndrome, and systemic lupus erythematosus. Some cases of other immune cytopenia (idiopathic thrombocytopenic purpura, Evans's syndrome) or lymphoproliferative disorders (large granular lymphocyte leukemia, malignant lymphoma) may be associated with AIN. Some cases of primary AIN occur, especially in children. The diagnosis of AIN depends on the demonstration of autoantibodies directed against neutrophil-specific antigens like CD16. The availability of granulocyte-colony stimulating factor for the treatment of AIN has been a major advance. In some cases, immunosuppressive therapy using prednisone, methotrexate, cyclosporine A must be added, especially in cases of secondary AIN.
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PMID:[Autoimmune neutropenias]. 1175 71

The cytotoxic depsipeptide kulokekahilide-1, which contains two unusual amino acids, 4-phenylvaline and 3-amino-2-methylhexanoic acid, was isolated from the cephalaspidean mollusk Philinopsis speciosa. Structure elucidation of kulokekahilide-1 was carried out by spectroscopic analysis and chemical degradation. The absolute stereochemistry was determined by Marfey analysis for amino acids and chiral HPLC analysis for hydroxy acids. All four stereoisomers of 4-phenylvaline and 3-amino-2-methylhexanoic acid, which were necessary for Marfey analysis, were synthesized by use of the Heck reaction and Evans's method, respectively. Kulokekahilide-1 showed cytotoxicity against P388 murine leukemia cells with an IC(50) value of 2.1 microg/mL.
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PMID:Kulokekahilide-1, a cytotoxic depsipeptide from the cephalaspidean mollusk Philinopsis speciosa. 1189 90

7,12-Dimethylbenz[a]anthracene (DMBA) elicits leukemia in Long-Evans rats (LE). This leukemia is mostly erythroblastic and 30% of leukemias have total and partial trisomy of #2 chromosome and the rest have diploid karyotype. The common duplication site is in 2q26-q34 and N-ras gene is located in 2q34. 7,8,12-Trimethylbenz[a]anthracene (TMBA) also induces similar leukemias. These leukemias reveal a highly specific mutation of N-ras gene as in human leukemias. N-ras mutation is induced 48h after DMBA treatment. Wild type N-ras allele is frequently lost in diploid leukemias but not in trisomy type. Therefore, a gene dosage problem related to the mutant N-ras gene is involved in development of leukemia. Some secondary genetic rearrangements involving abl and H-ras are also observed in cultured leukemia cells. DMBA-induced chromosome aberrations as well as leukemia are enhanced by erythropoietin and blocked by Sudan III given prior to DMBA treatment. This leukemia will provide an important tool for chemical carcinogenesis and leukemia studies.
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PMID:7,12-DMBA-induced rat leukemia: a review with insights into future research. 1244 76

According to recent publications 7,12-dimethylbenz[a]anthracene (DMBA) induces not only mammary cancer but also leukemia in Long-Evans (LE) rats. After treatment with DMBA, trisomy of the chromosome bearing N-ras and mutations in the codon 61 of different ras family genes are frequent. These alterations are already visible within 48 hours. Since there are very few data on ras genes' expression in the early stages of leukemogenesis, in our investigations LE rats were treated with DMBA and the expression of ras genes was measured within two days. DMBA was administered to outbred Long-Evans rats and the fluorescence intensity of the antibody recognizing the ras gene family was measured in femoral bone marrow cells 24 and 48 hours after the treatment. One of the bone marrow cell populations, separated by FSC and SSC, showed elevated ras gene expression at both 24 and 48 hours after the administration of the carcinogen. These results suggest that, besides the specific chromosomal aberrations and gene mutations, elevated ras gene expression could also be the marker of DMBA exposure.
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PMID:Flow cytometric analysis of DMBA-induced early in vivo ras expression. 1249 71

The anti-allergic action of buckwheat grain extract (BGE) was investigated using rodent experimental models. The oral, intraperitoneal and intradermal administration of BGE significantly inhibited the compound 48/80-induced vascular permeability documented by Evans blue extravasation. In addition, BGE showed potent inhibitory effect on passive cutaneous anaphylaxis (PCA) activated by anti-dinitrophenyl (DNP) IgE when orally administered. In an in vitro study, BGE revealed to possess inhibitory potential on the compound 48/80-induced histamine release from rat peritoneal mast cells (RPMC). Moreover, BGE inhibited the IL-4 and TNF-alpha mRNA induction by PMA and A23187 in human leukemia mast cells, HMC-1. Taken together, these results suggest that anti-allergic action of BGE may be due to the inhibition of histamine release and cytokine gene expression in the mast cells.
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PMID:Anti-allergic action of buckwheat (Fagopyrum esculentum Moench) grain extract. 1253 43

We describe an unusual case of acute paraplegia in a young adult (7.5-month-old) Long-Evans rat that resulted from a spontaneous T-cell lymphoma. At presentation, a neurologic exam revealed normal pelvic limb flexor reflexes, the absence of an anal reflex, and deep pain recognition. Radiographs did not identify any obvious spinal abnormality or osseous trauma, although the liver and spleen were prominent. Hematologic analysis disclosed leukocytosis with atypical lymphocytes. At necropsy, red, friable to gelatinous masses were found associated with the ventral aspect of the vertebral column at the levels of the thoracic and lumbar vertebrae. Impression smears of the mass revealed a monocytic cell population with cells averaging 7 to 10 microm in diameter and having scant cytoplasm and pleomorphic nuclei, characteristics consistent with a lymphoid neoplasm. Histologically, the neoplasm was unencapsulated, poorly demarcated and highly infiltrative, invading and effacing the bone marrow and epidural space of the vertebral column. Neoplastic cells also were identified in the femoral bone marrow, spleen, liver, iliac and sacral lymph nodes, and lung. Immunophenotyping showed the neoplasm to be of T-cell origin. Although the lymphoma did not invade the meninges of the spinal cord, its impingement on the central and peripheral nervous systems resulted in foci of Wallerian degeneration that contributed to the paraplegia. This case report highlights the importance of having lymphoma and leukemia among the differential diagnoses in cases of acute paralysis in rodents.
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PMID:Acute paraplegia in a young adult long-evans rat resulting from T-cell lymphoma. 1637 May 82

Stereoselective total syntheses of two novel conformationally restrained epothilone analogues are described. Evans asymmetric alkylation, Brown allylation, and a diastereoselective aldol reaction served as the key steps in the stereoselective synthesis of one of the two key fragments of the convergent synthetic approach. Enzyme resolution was employed to obtain the second fragment as a single enantiomer. The molecules were assembled by esterification, followed by ring-closing metathesis. In preliminary cytotoxicity studies, one of the analogues showed strong and selective growth inhibitory activity against two leukemia cell lines over solid human tumor cell lines. The precise biological mechanism of action and high degree of selectivity of this analogue remain to be examined.
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PMID:Total synthesis and selective activity of a new class of conformationally restrained epothilones. 1795 8

Niacin deficiency impairs poly(ADP-ribose) formation and enhances ethylnitrosourea (ENU)-induced carcinogenesis. Previous experiments were compromised by rapid progression of cancer, and the current study was designed with half the number of ENU doses. Weanling male Long-Evans rats were fed niacin deficient (ND), pair-fed (PF) control (30 mg nicotinic acid/kg), or pharmacological niacin (NA; 4 g nicotinic acid/kg) diets. After 2 wk, rats were gavaged every other day with ENU [30 mg/kg body weight (bw)] or vehicle (6 doses). Four days after the last dose of ENU, all rats were switched to AIN-93M diet and mildly feed restricted to maintain a constant food intake per bw. Rats were monitored for termination criteria and assessed for cancer development. Total cancers developed more rapidly in rats on the ND diet compared to those receiving high dose supplements of NA (P = 0.02; Gehan's generalized Wilcoxon test). Importantly, all of these differences occurred in the leukemias, especially the nonlymphocytic leukemia fraction (P = 0.008; Gehan's generalized Wilcoxon test), with incidences of 36%, 17%, and 11% in ND, PF, and NA rats, respectively. Because nonlymphocytic leukemias represent the majority of secondary cancers, these data support the concept that niacin supplementation may help protect cancer patients from the deleterious side effects of chemotherapy.
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PMID:Niacin supplementation decreases the incidence of alkylation-induced nonlymphocytic leukemia in Long-Evans rats. 1844 58


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