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)

Cytochrome P450 CYP2D6 polymorphism is an autosomal recessive trait associated with impaired debrisoquine metabolism in 5-10% of caucasian populations. This polymorphism has been associated with susceptibility to Parkinson's disease, bladder cancer, various forms of leukemia and possibly melanoma. In many other cancer forms, the data remained contradictory due to the technical limitations for identifying affected individuals (poor metabolizers). A recently developed polymerase chain reaction-based assay allows convenient screening of approximately 80% of known mutations. We have tested brain tumors correlated with chromosome 22 deviations for genetic polymorphism in the cytochrome P450 CYP2D6 locus localized on chromosome 22q13. Thirty-one meningioma samples were analyzed and the observed frequency of heterozygotes and homozygotes for the G to A mutation did not deviate significantly from the distribution in a normal population. These data are comparable to previous observations in for example breast and colon cancer and indicate that the CYP2D6 locus on chromosome 22q13 is not involved in the pathogenesis of meningiomas.
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PMID:Debrisoquine hydroxylase gene polymorphism in meningioma. 784 77

The injury associated with implantation of an inert gelatin matrix (gel foam) into normal mouse striatum induces a long-lived increase in binding of [3H]mazindol to presynaptic dopamine uptake sites, probably due to proliferation of striatal dopaminergic terminals. Because of the known effects of leukaemia inhibitory factor (LIF) on catecholaminergic cells, we tested the hypothesis that LIF may alter the striatal dopaminergic response to injury in vivo. Application of LIF to mouse striatum in a gel foam implant abolished the usual injury induced proliferation of dopamine uptake sites. The ability of LIF to prevent proliferation of dopamine terminals may have important implications for our understanding of neural regeneration, the aetiology of Parkinson's disease and its treatment by intrastriatal grafting.
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PMID:Leukaemia inhibitory factor prevents injury induced proliferation of striatal dopamine uptake sites. 854 84

Investigators have hypothesized that occupations involving electric and magnetic field exposure are associated with a variety of health problems, including neurological disease. The authors conducted a case-control study, and they used U.S. death certificates with occupational coding to compare male cases of Alzheimer's disease (n = 256), Parkinson's disease (n = 168), and amyotrophic lateral sclerosis (n = 114) with controls matched for age and calendar time. The authors selected controls in a 3:1 ratio to cases from persons who died of causes other than leukemia, brain cancer, and breast cancer. Overall associations with electrical occupations were modest (i.e., adjusted odds ratios of 1.2, 1.1, and 1.3 for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, respectively). Individual electrical occupations were associated more strongly with disease than overall electrical occupations, particularly amyotrophic lateral sclerosis, for which relative risks ranged from 2 to 5 across several job categories. The largest associations with all three diseases occurred for power plant operators.
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PMID:Electrical occupations and neurodegenerative disease: analysis of U.S. mortality data. 957 Mar 11

Available information on organochlorines and the chronic effects of exposure to them are set out. Organochlorinated compounds are the most persistent pesticides and can be found in all ecosystems. Although they are generally efficient in pest control, they are also a potent environment pollutant and can provoke health problems in man. The evidences of the carcinogenic potential of organochlorines are controversial and insufficient, but they have been related to an increase in the incidence of some kinds of tumors, such as leukemia and solid tumors. Reproductive effects, due to anti-androgenic and estrogenic action, on embryonic virilization, the incidence of abortion and the frequency of prematurity, have also been observed. The accumulation of the organochlorines in the adipous tissue is positively correlated to the increase in aging and could be implicated in the development of aging diseases, such as Parkinson's disease. The effects of pesticides on human health have not yet been completely elucidated. Genotoxicity is one of the most serious of the possible harmful effects caused by these compounds and calls for special attention in view of the irreversible nature of the process and to the long latency associated with its manifestation.
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PMID:[Delayed effects of organochlorine pesticides in man]. 987 30

1. The pathogenesis of the selective degeneration of the dopaminergic neurons in Parkinson's disease is still enigmatic. Recently we have shown that dopamine can induce apoptosis in postmitotic neuronal cells, as well as in other cellular systems, thus suggesting a role for this endogenous neurotransmitter and associated oxidative stress in the neuronal death process. 2. Dopamine has been shown to be capable of inducing DNA damage through its oxidative metabolites. p53 is a transcription factor that has a major role in determining cell fate in response to DNA damage. We therefore examined the possible correlation between dopamine-triggered apoptosis, DNA damage and levels of total phosphorylated p53 protein in cultured mouse cerebellar granule neurons. 3. Marked DNA damage and apoptotic nuclear condensation and fragmentation were detected within several hours of exposure to dopamine. An associated marked threefold increase in p53 phosphorylation was observed within this time window. Using a temperature-sensitive p53 activation system in leukemia LTR6 cells, were found that p53 inactivation dramatically attenuated dopamine toxicity. 4. We therefore conclude that DNA damage and p53 activation may have a role in mediating dopamine-induced apoptosis. Modulation of the p53 system may therefore have a protective role against the toxicity of this endogenous neurotransmitter and associated oxidative stress.
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PMID:The involvement of p53 in dopamine-induced apoptosis of cerebellar granule neurons and leukemic cells overexpressing p53. 1008 9

Stem cells are widely believed to have significant potential in the treatment of human disease. Comments such as '[stem cells]...could prove the Holy Grail in finding treatments for cancer, Parkinson's disease, diabetes, osteoporosis, spinal cord injuries, Alzheimer's disease, leukaemia and multiple sclerosis...transform[ing] the lives of hundreds of thousands of people' (Yvette Cooper, Public Health minister, quoted in The Times, December 16 2000, authors' italics) serve to reinforce the extraordinary expectations of stem cells, particularly in neurological disease. Stem cells, traditionally defined as clone forming, self-renewing, pluripotent, progenitor cells, have already proved themselves to be an invaluable source of transplantation material in several clinical settings, most notably malignant haematology, and attention is now turning to a wider variety of diseases in which there may be potential for therapeutic intervention with stem cell transplantation. Neurological diseases have been highlighted as a priority and this is understandable given their unenviable reputation for relentless progression and the paucity of disease-modifying treatments. However, it is important that the potential of stem cells to treat neurological disease is critically appraised if the hopes of patients and doctors are not to be raised without foundation.
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PMID:Stem cells for the treatment of neurological disease. 1465 41

The success of hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency (X-SCID) was a major breakthrough in the field of gene therapy. However, two patients treated with this gene therapy developed leukemia at a later time, and retroviral vector-mediated gene transfer was considered to trigger leukemogenesis; i.e. insertional mutagenesis caused activation of LMO 2 gene, which was one step toward leukemia development. To cope with this serious problem, basic studies are required to improve the safety of retroviral vectors and to develop the method for site-specific integration of transgenes. In addition, we have to develop technologies such as selective amplifier genes (SAGs), the system for selective expansion of transduced cells, in order to obtain therapeutic efficacy of hematopoietic stem cell gene therapy in many other disorders. Moreover, clinical applications of AAV vector are promising from the standpoint of safety issue, because this vector is derived from non-pathogenic virus. AAV vector is appropriate for gene transfer into neurons, muscles, and hepatocytes. For example, gene therapy for Parkinson's disease is investigated using AAV vectors. Genetic manipulation is also one of the indispensable technologies in the field of regeneration medicine, and further promotion of basic research is important.
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PMID:[Development and application of gene therapy technologies]. 1544 4

Five dipyridyl isomers, 2,2'-, 2,3'-, 2,4'-, 3,3'-, and 4,4'-dipyridyl, are products resulting from the pyrolytic degradation of tobacco products and degradation of the herbicide paraquat, and therefore may be present in the environment. In this article, the toxicological properties of these dipyridyl isomers in humans and animals are reviewed. Epidemiological studies suggest that cancerous skin lesions in workers involved in the manufacturing of paraquat may be associated with exposure to dipyridyl compounds. Experimental animal studies suggest that dipyridyl isomers may have several toxicological effects. Three of the dipyridyl isomers (the 2,2', 2,4', and 4,4' isomers) appear to be inducers of some metabolic enzymes. The 2,2'-dipyridyl isomer, an iron chelator, appears to influence vasospasm in primate models of stroke. The cytotoxic effects of 2,2'-dipyridyl on several leukemia cell lines have been reported, and a potent teratogenic effect of 2,2'-dipyridyl has been observed in rats. Based on the results of paraquat studies in experimental animal models, it has been proposed that paraquat may have deleterious effects on dopaminergic neurons. These findings support the epidemiological evidence that paraquat exposure may be associated with the development of Parkinson's disease. Studies designed to determine an association between paraquat exposure and Parkinson's disease are complicated by the possibility that metabolic changes may influence the neurotoxicity of paraquat and/or its metabolites. Preliminary unpublished data in mice show that 300-mg/kg doses of 2,2'-dipyridyl are neurotoxic, and 300-mg/kg doses of 2,4'- and 4,4'-dipyridyls are lethal. These results are consistent with earlier studies in Sherman rats using high 2,2'- and 4,4'-dipyridyl doses. New studies are needed to further explore the toxicological properties of dipyridyls and their potential public health impact.
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PMID:Toxicity of dipyridyl compounds and related compounds. 1556 May 68

Haematopoietic stem cell transplantation is an accepted curative therapy for many cancers and inherited non-malignant diseases, including bone marrow failure syndromes, haemoglobinopathies, and inborn errors of metabolism. Stem cells can be used from the bone marrow or blood of matched siblings or appropriately matched unrelated volunteers, but many patients do not have a suitably matched donor. Umbilical cord blood (UCB) has been successfully used as an alternative stem cell source. It has the advantage of tolerance for a degree of human leukocyte antigen (HLA) incompatibility not possible with adult bone marrow, resulting in greater likelihood of finding an appropriate match. UCB is also stored fully tested and cryopreserved, leading to rapid availability. Greatest clinical experience in UCB transplants has been in treating paediatric leukaemia. Results using well matched UCB grafts are equivalent or better than with unrelated bone marrow transplant. Cell dose and the degree of HLA matching are critical determinants in the success of UCB transplant. The use of UCB in older children and adult patients has been limited by the fixed, low cell dose available in a UCB unit, relative to recipient weight. This can be overcome by strategies such as using two or more UCB units. Early animal studies suggest that UCB may have the potential to differentiate into other cell types, including nervous tissue, and may in future play a role in the treatment of disorders such as Alzheimer disease and Parkinson disease.
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PMID:No longer a biological waste product: umbilical cord blood. 1661 41

Estrogens can be converted to electrophilic metabolites, particularly the catechol estrogen-3,4-quinones, estrone(estradiol)-3,4-quinone [E(1)(E(2))-3,4-Q], which react with DNA to form depurinating adducts. These adducts are released from DNA to generate apurinic sites. Error-prone repair of this damage leads to the mutations that initiate breast, prostate, and other types of cancer. The reaction of E(1)(E(2))-3,4-Q with DNA forms the depurinating adducts 4-hydroxyE(1)(E(2))-1-N3adenine [4-OHE(1)(E(2))-1-N3Ade] and 4-OHE(1)(E(2))-1-N7guanine(Gua). These two adducts constitute >99% of the total DNA adducts formed. The E(1)(E(2))-2,3-Q forms small amounts of the depurinating 2-OHE(1)(E(2))-6-N3Ade adducts. Reaction of the quinones with DNA occurs more abundantly when estrogen metabolism is unbalanced. Such an imbalance is the result of overexpression of estrogen-activating enzymes and/or deficient expression of deactivating (protective) enzymes. Excessive formation of E(1)(E(2))-3,4-Q is the result of this imbalance. Oxidation of catechols to semiquinones and quinones is a mechanism of tumor initiation not only for endogenous estrogens, but also for synthetic estrogens such as hexestrol and diethylstilbestrol, a human carcinogen. This mechanism is also involved in the initiation of leukemia by benzene, rat olfactory tumors by naphthalene, and neurodegenerative diseases such as Parkinson's disease by dopamine. In fact, dopamine quinone reacts with DNA similarly to the E(1)(E(2))-3,4-Q, forming analogous depurinating N3Ade and N7Gua adducts. The depurinating adducts that migrate from cells and can be found in body fluids can also serve as biomarkers of cancer risk. In fact, a higher level of estrogen-DNA adducts has been found in the urine of men with prostate cancer and in women with breast cancer compared to healthy controls. This unifying mechanism of the origin of cancer and other diseases suggests preventive strategies based on the level of depurinating DNA adducts that generate the first critical step in the initiation of diseases.
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PMID:Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture. 1726 77


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