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)

Nutritional intervention in the cancer patient [e.g., total parenteral nutrition (TPN)] might improve durable survival because of increased tolerance to aggressive tumor therapy. To determine whether this assumption is correct, 42 patients with diffuse histiocytic lymphoma were induced with prednisone, high-dose methotrexate, Adriamycin, cyclophosphamide, and VP-16 (ProMACE). Nitrogen mustard-vincristine-procarbazine-prednisone (MOPP) consolidation was then used, followed by late intensification with ProMACE. Patients were selected randomly to receive adjuvant TPN or a standard diet during ProMACE-MOPP treatment. While TPN patients had a greater median weight gain than did control patients, lean body mass and degree of myelosuppression did not improved as a consequence of TPN. There was no significant difference in tumor response or survival between TPN and control patients, whether or not the patients were initially malnourished. In a second trial, 32 young patients with metastatic or other poor-prognosis sarcomas were randomly allocated to receive TP or a standard diet as an adjunct to one very intensive course of combination chemotherapy or chemotherapy plus total body irradiation; autologous marrow transplantation was used with gain than did controls but remained in a negative nitrogen balance. Response rates and median durable survival did not differ between the two groups. In both trials, the maximum nutritional support permitted by currently available technology was offered. Thus, the limiting factor may not be nutritional status but rather the intrinsic biology of the tumors and the limitations of their response to current therapy. In in vitro studies of the possible influence of nutrition on cancer treatment, we have compared sublines of P388 murine leukemia cells which are sensitive or resistant to Adriamycin. The difference in drug sensitivity correlated with differences in lipid composition, with more intracellular lipid, and with greater membrane rigidity in the resistant cells. Resistant cells have a relatively poor transport of drug into the cell; moreover, intracellular Adriamycin is sequestered in lipid depots away from DNA. These results suggest one possible relationship between nutritional phenomena and drug sensitivity.
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PMID:Controlled clinical trials of nutritional intervention as an adjunct to chemotherapy, with a comment on nutrition and drug resistance. 679 96

The cytotoxicity of the antitumour nitrosoureas BCNU and CCNU and the isocyanates which they liberate (chloroethylisocyanate and cyclohexylisocyanate respectively) has been measured utilising an in vitro-in vivo bioassay. Lines of the TLX5 lymphoma and L1210 leukaemia were used which were either sensitive or resistant to nitrosoureas in vivo. An estimated logarithmic cell kill produced by each compound in vitro (before injecting the cells into animals) was calculated by reference to assays of the survival time of animals given from 2 X 10(5) to 2 X 10(0) cells of each line. Resistance to both BCNU and CCNU was observed in vitro in the cell lines of the TLX5 lymphoma made resistant to either BCNU or a dimethyltriazene in vivo. The latter tumour was cross-resistant in vivo to nitrosoureas. Resistance in vitro to nitrosoureas was also observed in a line of L1210 leukaemia which had had resistance to BCNU induced in vivo. The nitrosourea resistant TLX5 lymphomas were cross-resistant in vitro to both cyclohexylisocyanate and chloroethylisocyanate whereas the nitrosourea resistant L1210 line showed no cross-resistance to cyclohexylisocyanate and marginal cross-resistance to chloroethylisocyanate. The results suggest that the TLX5 lymphoma, which is naturally resistant to alkylating agents of the 2-chloroethylamine type, may be sensitive to in vivo to nitrosoureas as a consequence of the intracellular release of isocyanates. This hypothesis was supported by the finding that the resistant TLX5 lymphoma showed no cross-resistance to other electrophilic agents, for example formaldehyde, monomethyltriazene or HN2. The transport of nitrosoureas into the sensitive and resistant cell lines was similar in profile and there was no difference in the concentration of non-protein thiols.
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PMID:The role of isocyanates in the toxicity of antitumour haloalkylnitrosoureas. 713 75

Recent evidence has established an important role for leukemia inhibitory factor (LIF) as hematopoietically active cytokine. The present study utilized two different murine bone marrow stromal cell lines, +/+-1.LDA11 and MBA-13, to define regulatory mechanisms of LIF messenger RNA (mRNA) induction. LIF mRNA was not detected in uninduced stromal cells under serum-free conditions. Incubation with interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha) or the cAMP analogue 8-bromoadenosine 3':5'-monophosphate (8BrcAMP) resulted in weakly induced LIF mRNA. Coincubation of combinations of the stimuli increased LIF mRNA expression additively. LIF mRNA stability, even after stimulation, was low with a half-life of about 30 min, suggesting a functional role for known AU-rich motifs in the 3' untranslated LIF mRNA region in mediating this instability. This possibility was further supported by the ability of cycloheximide to increase mRNA levels without affecting transcription. Transcriptional activation was found to be the main mechanism leading to LIF mRNA expression by IL-1, by TNF-alpha, and by 8BrcAMP. These stimuli appeared to act additively in this regard, suggesting involvement of distinct transcription factors. Induction of transcription was detected 45 min post-stimulation and showed peak levels at 90 min. Kinetics of LIF transcriptional activation showed similarity with the kinetics of the transcription factors, jun-B and c-fos, suggesting a possible role for these proteins or other early response genes in events leading to LIF expression.
Leukemia 1993 Apr
PMID:LIF mRNA expression is transcriptionally regulated in murine bone marrow stromal cells. 846 40

The triphenolic metabolite of benzene, 1,2,4-benzenetriol (BT), is readily oxidized to its corresponding quinone via a semiquinone radical. During this process, active oxygen species are formed that may damage DNA and other cellular macromolecules. The ability of BT to induce micronuclei (MN) and oxidative DNA damage has been investigated in both human lymphocytes and HL60 cells. An antikinetochore antibody based micronucleus assay was used to distinguish MN containing kinetochores and potentially entire chromosomes (kinetochore-positive, K+) from those containing acentric chromosome fragments (kinetochore-negative, K-). BT increased the frequency of MN formation twofold in lymphocytes and eightfold in HL60 cells with the MN being 62% and 82% K+, respectively. A linear dose-related increase in total MN, mainly in K(+)-MN, was observed in both HL60 cells and lymphocytes. Addition of copper ions (Cu2+) potentiated the effect of BT on MN induction threefold in HL60 cells and altered the pattern of MN formation from predominantly K+ to K-. BT also increased the level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a marker of active oxygen-induced DNA damage. Cu2+ again enhanced this effect. Thus, BT has the potential to cause both numerical and structural chromosomal changes in human cells. Further, it may cause point mutations indirectly by generating oxygen radicals. BT may therefore play an important role in benzene-induced leukemia.
Environ Mol Mutagen 1993
PMID:Benzene metabolite, 1,2,4-benzenetriol, induces micronuclei and oxidative DNA damage in human lymphocytes and HL60 cells. 849 Dec 13

V(D)J recombinase is normally involved in the highly regulated rearrangement of immunoglobulin and T-cell-receptor gene segments (in B and T cells, respectively) to form functional antibody genes and T-cell-receptor genes. Occasionally, this tightly controlled process acts on inappropriate places in the genome and results in deletions and translocations. Some of these illegitimate V(D)J recombinase-mediated events have been implicated in the genetic changes associated with several forms of leukemia and lymphoid malignancy. We have developed a sensitive, specific polymerase chain reaction (PCR)-based assay to quantify such events in the peripheral blood cells of humans. This assay detects a V(D)J recombinase-mediated deletion in the hprt gene, which codes for a housekeeping enzyme and is not implicated in cancer development. Alterations in this gene serve as a surrogate indicator for these illegitimate events, which may be occurring throughout the genome. The assay involves a hemi-nested PCR with two sets of primers. Multiple replicates of genomic DNA (each representing 4 x 10(5) cells) are amplified with specific primers under conditions in which a single copy will give a detectable PCR product. Poisson statistics are then used to estimate the deletion mutant frequency. The frequency of cells with the hprt deletion among 20 healthy young adults ranged from <1.3 x 10(-7) to 4.1 x 10(-7) and was compared with the frequency of t(14;18) previously determined in these same individuals. No correlation was found between the frequencies of these two measures of genomic rearrangement. The DNA sequences at the deletion junctions were determined and provided evidence for multiple independent mutations in some individuals. This assay may serve as a biomarker for the level of illegitimate V(D)J recombination occurring in peripheral blood cells of humans.
Environ Mol Mutagen 1997
PMID:Quantification of hprt gene deletions mediated by illegitimate V(D)J recombination in peripheral blood cells of humans. 902 Mar 4

Silver iodide was evaluated for mutagenicity in the Ames/microsome test (strains TA 1535, TA 102, TA 97, and TA 98) and for the ability to induce Sister Chromatid Exchanges (SCE) in human cultured lymphocytes and in P388 lymphocytic leukemia cells cultured in the mouse peritoneal cavity. From the cytogenetic in vitro studies, it was observed that silver iodide, either in acetone solutions or as a suspension with polyacrilamide, scarcely causes a doubling effect on SCEs at nearly toxic concentrations (1 microg/ml). Such a doubling effect by silver iodide on SCEs in P388 leukemia cells in vivo was not achieved even after using 100 microg/g mouse body weight. In the Ames/microsome test actually a doubling effect on revertants was only isolately achieved with 30 microg/ml in TA 102 (S9-) and at 150 microg/ml in TA 97 (S9+) doses, which appear to be nearly toxic for bacteria.
Teratog Carcinog Mutagen 1998
PMID:Lack of genotoxicity of silver iodide in the SCE assay in vitro, in vivo, and in the Ames/microsome test. 1005 65

Enhanced sister chromatid exchange (SCE) frequency by either melphalan (Mel) or epirubicin (Epir) was observed when human lymphocytes were exposed in vitro to 9-nitro-20(S)-camptothecin (9NC). A correlation was observed between the magnitude of the SCE response and the depression of the cell proliferation index. The antitumor activity of Mel and of 9NC was tested on leukemia P-388-bearing mice. The two chemicals in combination enhance antitumor activity in a synergistic manner. Therefore, the in vivo antitumor effect of Mel in conjunction with 9NC appears to correlate well with the in vitro synergistic effect on SCE induction caused by the combined Mel plus 9NC treatment. Teratogenesis Carcinog. Mutagen. 20:141-146, 2000.
Teratog Carcinog Mutagen 2000
PMID:Enhanced cytogenetic and antitumor effects by 9-nitrocamptothecin and antineoplastics. 1082 Apr 24

The alkylating agent, nitrogen mustard (HN2), is thought to cause apoptosis through production of free oxygen radicals. To explore the mechanism of HN2-induced apoptosis, we utilized ebselen, a selenoorganic compound with potent antioxidant activity. We examined whether ebselen would inhibit apoptosis in BALB/c mouse spleen lymphocytes and human MOLT-4 leukemia cells treated with HN2 (2.5 microM) in vitro. Non-toxic concentrations (<50 microM) of ebselen were found to prevent HN2-induced apoptosis of murine lymphocytes in a dose-dependent manner, as measured by cell viability, hypodiploid DNA formation, and phosphatidylserine externalization. However, ebselen was ineffective at preventing spontaneous apoptosis in these cells, pointing to the selectivity of its action. Furthermore, pretreatment with ebselen at 1-10 microM for 72 hr protected MOLT-4 cells from HN2-induced apoptosis and maintained cell viability and proliferation as monitored by the above-mentioned parameters. This was accompanied by the preservation of mitochondrial transmembrane potential and elevated glutathione levels and by a blockage of caspase-3 and -9 activation. In vivo, ebselen also had a marked protective effect against spleen weight loss associated with lymphocyte apoptosis in mice treated by HN2. Therefore, ebselen provides an efficient protection against HN2-induced cell death in normal and tumoral lymphocytes and might prove useful as an antidote against alkylating agents.
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PMID:Prevention of nitrogen mustard-induced apoptosis in normal and transformed lymphocytes by ebselen. 1107 38

The hypothesis that exposure to domestic radon raises the risk for leukemia and other nonpulmonary cancers has been proposed and tested in a number of epidemiologic studies over the past decade. During this period, interest in this hypothesis was heightened by evidence of increased frequencies of mutations at the hypoxanthine guanine phosphoribosyl transferase (hprt) gene in persons exposed to domestic radon (Bridges BA et al. [1991]: Lancet 337:1187-1189). An extension of this study (Cole J et al. [lsqb[1996]: Radiat Res 145:61-69) and two independent studies (Albering HJ et al. [1992[: Lancet 340:739; Albering HJ et al. [1994[: Lancet 344:750-751) found that hprt mutant frequency was not correlated with domestic radon exposure, and two well-designed epidemiologic studies showed no evidence of a relation between radon exposure and leukemia in children or adults. In this report, we present additional data from a study of Colorado high school students showing no correlation between domestic radon exposure and hprt mutant frequency. We use reanalyses of previous studies of radon and hprt mutant frequency to identify problems with this assay as a biomarker for domestic radon exposure and to illustrate difficulties in interpreting the statistical data. We also show with analyses of combined data sets that there is no support for the hypothesis that domestic radon exposure elevates hprt mutant frequency. Taken together, the scientific evidence provides a useful example of the problems associated with analyzing and interpreting data that link environmental exposures, biomarkers, and diseases in epidemiologic studies.
Environ Mol Mutagen 2001
PMID:hprt mutant frequencies, nonpulmonary malignancies, and domestic radon exposure: "postmortem" analysis of an interesting hypothesis. 1117 Feb 37

Accumulation of genetic damage in long-lived cell populations with proliferative capacity is implicated in tumorigenesis. Hematopoietic stem cells (hsc) maintain lifetime hematopoiesis, and recent studies demonstrate that hsc in leukemic patients are cytogenetically aberrant. We postulated that exposure to agents associated with increased leukemia risk would induce genomic changes in cells in the hsc compartment. Aneusomy involving chromosomes 2 and 11 in sorted hsc (Lin(-)c-kit(+)Sca-1(+)) and maturing lymphoid and myeloid cells from mice that received topical doses of benzene (bz) or trichloroethylene (TCE) was quantified using fluorescence in situ hybridization. Six days after bz or TCE exposure, aneuploid cells in the hsc compartment increase four- to eightfold in a dose- and schedule-independent manner. Aneuploid lymphoid and myeloid cells from bz- and TCE-treated mice approximate controls, except after repeated benzene exposures. Aneuploid cells are more frequent in the hsc compartment than in mature hematopoietic subpopulations. Hematotoxicity was also quantified in bz- and TCE-exposed hematopoietic subpopulations using two colony-forming assays: CFU-GM (colony-forming units/granulocyte-macrophage progenitors) and CAFC (cobblestone area-forming cells). Data indicate that bz is transiently cytotoxic (< or =1 week) to hsc subpopulations, and induces more persistent toxicity (>2 weeks) in maturing, committed progenitor subpopulations. TCE is not hematotoxic at the doses applied. In conclusion, we provide direct evidence for induction of aneuploidy in cells in the hsc compartment by topical exposure to bz and TCE. Disruption of genomic integrity and/or toxicity in hsc subpopulations may be one step in leukemic progression.
Environ Mol Mutagen 2001
PMID:Dermal benzene and trichloroethylene induce aneuploidy in immature hematopoietic subpopulations in vivo. 1131 36


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