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)

Fifty-nine towns in Iowa with single source drinking water supplies were stratified on the basis of radium content in finished non-softened water to test the hypothesis of an association with total or acute myeloid leukemia. Fourteen towns had radium concentrations in drinking water exceeding the EPA safety limit of 5 picocuries per liter (pCi/L). A small increasing trend existed for total leukemia with increased radium content in drinking water that is in accordance with either the hypothesis of no effect or of a small effect.
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PMID:Leukemia incidence and radioactivity in drinking water in 59 Iowa towns. 240 41

Essential fatty acids, from which PG derive, can participate in development and regulation of immune responses and have been shown to suppress inflammation and tissue injury in animal models. In this report, we investigate the effects of the immediate (DGLA, precursor to PGE1), arachidonic acid (AA, PGE precursors, dihomogamma linolenic acid (DGLA, precursor to PGE1), arachidonic acid (AA, precursor to PGE2), and eicosapentaenoic acid (EPA, precursor to PGE3) on IL-2 production by PHA-stimulated human PBMC. DGLA and AA inhibited IL-2 production in a dose-dependent manner: half-maximal inhibition was obtained by using the fatty acids at the dose of 10 micrograms/ml without significant effects on cell viability. EPA inhibited IL-2 production by PBMC of only some donors. Incubation of cells in the presence of oleic, stearic, and palmitic acids, which are not PG precursors, did not affect mitogen-induced IL-2 production. A progressive increase in incorporation of DGLA into cellular lipids was observed over a 48-h incubation period. IL-2 production was reduced also when PBMC were pretreated overnight with DGLA or AA and washed before exposure to PHA. Whereas addition of the cyclo-oxygenase inhibitor, indomethacin, at the time of mitogenic stimulation led to increased IL-2 production and prevented mitogen- and fatty acid-induced increases in PGE release, it had no significant effect on the capacity of the fatty acids to suppress IL-2 production. Time course experiments showed that DGLA and AA inhibited IL-2 production even at times of minimal or no PGE release by the treated cultures. Moreover, DGLA and AA inhibited IL-2 production by the human leukemia T cell line Jurkat which, when appropriately induced, is able to release high levels of IL-2 in the absence of accessory cells and measurable PGE production. Taken together, these data indicate that essential fatty acids inhibit IL-2 production directly without conversion into their cyclo-oxygenase pathway products, and suggest that human lymphocyte function may be altered profoundly by small changes in their fatty acid profile.
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PMID:Prostaglandin E precursor fatty acids inhibit human IL-2 production by a prostaglandin E-independent mechanism. 254 87

A cultured subline (P388/ADM) of mouse P388 leukemia resistant to doxorubicin, vinblastine, vincristine, dactinomycin, and daunorubicin became sensitive again when treated with noncytotoxic doses of either of two synthetic isoprenoids: N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB-ethylenediamine) and N-(p-methylbenzyl)decaprenylamine X HCI (PMB-decaprenylamine). The isoprenoids also reversed resistance to doxorubicin and vincristine in a cultured vincristine-resistant P388 leukemia subline (P388/VCR). Median lethal doses (LD50) for PMB-decaprenylamine and SDB-ethylenediamine administered ip were 123 and 350 mg/kg against mice, whereas the LD50 for verapamil, another modifier of cellular drug resistance, was about 7.6 mg/kg. In vivo experiments with P388/VCR-bearing mice showed that both SDB-ethylenediamine and verapamil overcame vincristine resistance, but PMB-decaprenylamine showed only slight activity. SDB-ethylenediamine was especially effective, overcoming the vincristine resistance at 1 mg drug/kg. Since the structure of SDB-ethylenediamine resembles that of verapamil, a calcium-blocking agent that overcomes drug resistance, it was checked for calcium-blocking activity. However, calcium channel-blocking activity was not observed with 20 micrograms isoprenoid/ml, whereas calcium channel activity was completely blocked by 1 microgram verapamil/ml.
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PMID:Overcoming drug resistance in cancer cells with synthetic isoprenoids. 345 80

The literature on cell transformation by chemical carcinogens has been critically reviewed. This subject is highly relevant to carcinogenesis in vivo, because the phenotypic changes that are collectively referred to as cell transformation usually involve the acquisition of tumorigenicity on inoculation into suitable rodent hosts. The systems chosen for review fall into 3 categories: cell strains (cells with a limited lifespan); cell lines (cells with an unlimited lifespan); and oncogenic viral-chemical interactions involving cells (Fischer rat embryo cells expressing an endogenous retrovirus, mouse embryo cells expressing the AKR leukemia virus, chemical enhancement of a simian adenovirus, SA7 transformation of Syrian hamster or rat embryo cells). Of the entire literature reviewed, 117 papers have been accepted for data abstraction by pre-defined criteria; these include 41 references to cell strains, 40 in cell lines, and 38 in viral-chemical interactions including cells. Because different systems have been reviewed, it would be meaningless to group all the compounds. The overall summary of the systems is as follows (many compounds have been tested in more than one system and, hence, are duplicated in these totals). (Chart: see text) In general, there is a reasonably good correlation between the results of the cell transformation systems and in vivo carcinogenesis. However, the many deficiencies of the EPA Merged Carcinogen List preclude definitive comparisons. Moreover, a number of 'false negatives' were obtained in systems that did not employ external metabolic activation. Further validation of all systems is required, but it seems very probable that several cell transformation systems will become valuable in assaying (with reasonable time and cost) the carcinogenic potential of environmental chemicals.
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PMID:Cell transformation by chemical agents--a review and analysis of the literature. A report of the U.S. Environmental Protection Agency Gene-Tox Program. 633 91

After 30 years of experience with human exposure to dichlorvos (DDVP) in the home, workplace, and sickroom, the U.S. EPA has published its intent to revoke the food additive registration of this cholinesterase-inhibiting insecticide. The basis for the Agency action is the result of the National Toxicology Program (NTP) toxicology and carcinogenesis study of DDVP in rats and mice (NTP Technical Report No. 342, September 1989). In those experiments the NTP considered the result in the female mouse portion of the study to afford unequivocal evidence of carcinogenicity. The NTP considered the interpretations of the male and female rat and the male mouse studies to be less than clear. Despite the NTP interpretation, the EPA considers the male rat data (increased incidence of mononuclear cell leukemia) to be sufficient to warrant the regulatory change. The purpose of this report is to summarize a review of the interpretation of the NTP data and to assess the predictive validity of the results relative to potential human health impact. Critical review of experimental data indicates that the evidence for a carcinogenic effect of DDVP in animals is equivocal. Further, DDVP possess no in vivo mutagenic activity in mammalian assay systems and it bears no significant structural similarity to known carcinogens. Therefore, a weight-of-the-evidence analysis leads to the conclusion that DDVP poses neither mutagenic nor carcinogenic risks to humans exposed under normal conditions of use of foreseeable conditions of misuse.
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PMID:Dichlorvos carcinogenicity: an assessment of the weight of experimental evidence. 772 38

Several proteinases from different multigene families have been implicated in the uterine invasion required for establishment of pregnancy in some mammals. In this study, the expression of matrix metalloproteinase gelatinase B (MMP-9), urokinase-type plasminogen activator (uPA) and their inhibitors was investigated during early mouse embryo development. Transcripts for tissue inhibitors of metalloproteinases (TIMP-1,-2,-3) and uPA receptor were detected throughout pre- and peri-implantation development whilst MMP-9 and uPA mRNAs were first detected in peri-implantation blastocysts associated with the invasive phase of implantation. Through use of in situ hybridization, it was shown that MMP-9 transcripts were strongly expressed in the network of trophoblast giant cells at the periphery of implanting 7.5 day embryos and TIMP-3 transcripts were strongly expressed in the decidua immediately adjacent to the implanting embryo. uPA transcripts were preferentially expressed in the ectoplacental cone and its derivatives. Because these proteinases are regulated by growth factors and cytokines in other tissues, the effect of leukaemia inhibitory factor (LIF) and epidermal growth factor (EGF) on their activity was investigated. Both LIF and EGF, like the proteinases, have been implicated in peri-implantation development. Blastocysts collected on day 4 of pregnancy were cultured 2 days in TCM 199 + 10% fetal bovine serum to allow outgrowth followed by 24 hour culture in defined media containing either LIF or EGF. Conditioned media were assayed for uPA activity by a chromogenic assay and MMP activity by gelatin zymography. Both LIF and EGF stimulated uPA and MMP-9 activity in blastocyst outgrowths after 3 days of culture (day 7). Proteinase activity was assayed again at the 5th to 6th day of culture (day 9 to 10). EGF was found to have no effect whereas LIF decreased production of both proteinases. These results demonstrate that proteinase activity in early embryos can be regulated by growth factors and cytokines during the implantation process and, in particular, they demonstrate the possible involvement of LIF in establishment of the correct temporal programme of proteinase expression.
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PMID:Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor. 774 17

The potential human carcinogenicity of PCE has been the subject of study for many years, yet the largest and most recent occupational studies have not reported any increased risk of leukemia in PCE-exposed groups, let alone a risk of the magnitude suggested by Aschengrau et al. The EPA's own Science Advisory Board concluded in 1991 that PCE is a chemical "for which there is no compelling evidence of human cancer risk, accompanied by animal data of carcinogenicity whose extrapolation to humans is ambiguous." Given this background, it is not plausible that a leukemia risk of the magnitude reported by Aschengrau et al. should exist but not have been found among highly exposed occupational groups. Aschengrau et al. could contribute to our understanding of this inconsistency by presenting the additional data analysis that I have suggested.
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PMID:Apparent increased risk of leukemia in their highest category of exposure to tetrachloroethylene (PCE) in drinking water. 821 91

A methodology recently developed by the U.S. EPA for estimating the carcinogenic risks from ionizing radiation is described. For most cancer sites, the risk model is one in which age-specific, relative risk coefficients are obtained by taking a geometric mean of the coefficients derived from the atomic bomb survivor data using two different methods for transporting risks from the Japanese to the U.S. population. The risk models are applied to estimate organ-specific risks per unit dose for a stationary population with mortality rates governed by 1980 U.S. vital statistics. With the exception of breast cancer, low-LET radiogenic cancer risk estimates are reduced by a factor of 2 at low doses and dose rates compared to acute high dose exposure conditions. For low dose (or dose rate) conditions, the risk of inducing a premature cancer death from uniform, whole body, low-LET irradiation is calculated to be 5.1 x 10(-2) Gy-1. Neglecting nonfatal skin cancers, the corresponding incidence risk is 7.6 x 10(-2) Gy-1. High-LET (alpha particle) risks are presumed to increase linearly with dose and to be independent of dose rate. High-LET risks are estimated to be 20 times the low-LET risks estimated under low dose rate conditions, except for leukemia and breast cancer where RBEs of 1 and 10 are adopted, respectively.
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PMID:Estimates of radiogenic cancer risks. 779 Feb 17

In our previous report (Shikano, M., Masuzawa, Y. and Yazawa, K. (1993) J. Immunol. 150, 3525-3533), we described that the enrichment of docosahexaenoic acid (DHA, 22:6(n - 3)) reduces both arachidonic acid (AA, 20:4(n - 6)) release and platelet-activating factor (PAF) synthesis in human eosinophilic leukemia cells, Eol-1. Since no DHA release was observed in response to Ca-ionophore stimulation, we presumed that the phospholipase A2 (PLA2) responsible for AA release and PAF synthesis can not hydrolyze the DHA moiety of phospholipids. In the present paper, we examined whether DHA-containing diacyl- and alkenylacylglycerophosphoethanolamine (DHA-diacylGPE and DHA-alkenylacyGPE) are susceptible to the action of AA-preferential 85 kDa cytosolic phospholipase A2 (cPLA2) from rabbit platelets in comparison with AA and eicosapentaenoic acid (EPA, 20:5(n - 3)) derivatives. When diacylGPE was used as a substrate, DHA release was almost negligible under the assay condition that allowed AA and EPA to be liberated at the rates of 4.3 mumol/min per mg protein and 2.5 mumol/min per mg protein, respectively. On the other hand, 14 kDa type II PLA2 hydrolyzed DHA-diacylGPE as well as AA-diacylGPE and EPA-diacylGPE. When DHA-diacylGPE and AA-diacylGPE were mixed at equimolar concentrations, DHA release by cPLA2 was not observed and AA release was reduced to 32% in the case without DHA-diacylGPE. This indicated that DHA-diacylGPE is a poor substrate but possesses the inhibitory activity for cPLA2. cPLA2 does not clearly discriminate between AA-alkenylacylGPE and AA-diacylGPE. As in the case using diacylGPE as a substrate, DHA-alkenylacylGPE was completely discriminated from AA-alkenylacylGPE by cPLA2. The roles of DHA and cPLA2 in the synthesis of lipid mediators will be discussed in relation to the new aspects of the substrate specificity of cPLA2 provided here.
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PMID:Complete discrimination of docosahexaenoate from arachidonate by 85 kDa cytosolic phospholipase A2 during the hydrolysis of diacyl- and alkenylacylglycerophosphoethanolamine. 818 Feb 47

This report updates the risk assessment by Crump and Allen (1984) for benzene-induced leukemia that was used by OSHA (1987) to support its reduction of the permissible exposure limit (PEL) to 1 ppm and that also was the basis for EPA's (1985) interim "unit risk" for benzene. The present study derives new risk estimates using data from follow-up through 1987 (whereas the earlier assessment only had follow-up available through 1978), and using new exposure estimates for this cohort developed by Paustenbach et al. (1992) that account for a number of factors that were unknown or not fully evaluated in earlier exposure assessments. There was a significant excess of acute myelocytic or acute monocytic leukemia (AMML, the only forms of acute nonlymphatic leukemia observed) in this cohort, and this end point also exhibited a strong dose-response trend. AMML was the only hematopoietic or lymphatic cancer that was clearly linked to benzene exposure. However, quantitative estimates of risk based on modeling either AMML or all leukemia differed by only 20%. Differences between the two Pliofilm plant locations in the occurrence of AMML were not statistically significant (.12 < or = p < or = .21) after differences in levels of benzene exposure were taken into account. The Paustenbach et al. exposures predicted a quadratic dose response, based on a measure of exposure that weighted intensity of exposure more heavily than duration of exposure. The best-fitting quadratic models predicted an additional lifetime risk of a benzene-related death from 45 yr of exposure to 1 ppm of between 0.020 and 0.036 per thousand. Statistical confidence intervals (90%) on these estimates were barely wide enough to include risk estimates based on linear dose response models. These linear models predicted risks of between 1.6 and 3.1 per thousand.
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PMID:Risk of benzene-induced leukemia: a sensitivity analysis of the pliofilm cohort with additional follow-up and new exposure estimates. 820 57


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