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

Iodothyronine 5'-deiodinase isoenzymes generate the thyroid hormone 3,3',5-triiodothyronine from the prohormone L-T4. Basal and retinoic acid (RA)-induced type I 5'-deiodinase (5'DI) activities were studied in human thyroid carcinoma cell lines. In the follicular thyroid carcinoma line FTC-133, nanomolar concentrations of 9-cis, 13-cis-, and all-trans-RA induced 5'DI activity. Kinetics with all-trans-RA revealed 5'DI stimulation after 1 day and a maximal effect after 3 days. Increased abundance of the p27 5'DI subunit was demonstrated after RA treatment by N-bromoacetyl-[125I]T4 affinity labeling. Actinomycin-D and cycloheximide blocked RA-mediated induction. RA stimulated 5'DI activity to a lesser extent in FTC-238 cells, whereas neither basal 5'DI activity nor stimulation by RA was found in anaplastic thyroid carcinoma, human lung, or leukemia cell lines. Steady state messenger ribonucleic acid levels of RA receptor-alpha and -beta were increased after incubation of FTC-133 cells with all-trans-RA. The high 5'DI activity of differentiated rat thyroid FRTL-5 cells was not further induced by RA. Butyrate did not alter 5'DI, but increased the activity of the differentiation marker alkaline phosphatase in FTC-133 and FTC-238 cells. T4 and T3 had no effect on basal or RA-stimulated 5'DI activity. These data suggest that expression and retinoid induction of 5'DI may serve as a sensitive and functional differentiation parameter of follicular thyroid carcinoma cells.
 ...
PMID:Retinoids stimulate type I iodothyronine 5'-deiodinase activity in human follicular thyroid carcinoma cell lines. 807 63

Effects of fatty acids on accumulation and secretion of histamine in rat basophilic leukemia RBL-2H3 cells and leukotriene release from peritoneal exudate cells isolated from Wistar rats were examined in relation to the manifestation of type I allergic reactions. When RBL-2H3 cells were cultured for 24 h in the presence of 1 mM short chain fatty acids, a marked increase in histamine accumulation was observed, especially with butyric acid. In addition, Ca-ionophore A23187-stimulated histamine release was enhanced in the cells treated with 0.1 mM mono to hexa unsaturated fatty acids with 18 to 22 carbon-chains. On the other hand, LTB4 release from rat peritoneal exudate cells was inhibited in the presence of polyunsaturated fatty acids, both n-6 and n-3, having more than 3 double bonds. Inhibitory activity was enhanced by an increase in the number of double bonds, and docosahexaenoic acid (DHA) exerted the highest activity with complete inhibition at 0.1 mM and 35.5% inhibition even at 10 microM. A hydrophobic radical scavenger (9,10-diphenylanthracene) and two antioxidants (butyrated hydroxytoluene and alpha-tocopherol) inhibited the production of LTB4, but hydrophilic counterparts (mannitol and ascorbic acid) did not. These results suggest that lipophilic anti-oxidative agents, as well as PUFA, inhibit the production of LTB4.
 ...
PMID:Effects of fatty acids on accumulation and secretion of histamine in RBL-2H3 cells and leukotriene release from peritoneal exudate cells isolated from Wistar rats. 890 31

A derivative of butyric acid, pivalyloxymethyl butyrate (AN-9), inhibited the proliferation and induced apoptosis of mouse monocytic leukaemia Mm-A cells, although sodium butyrate, but not AN-9, induced differentiation of the cells. AN-9 and DNA-specific antineoplastic agents synergistically inhibited the growth of Mm-A cells, and the simultaneous treatment was required to evoke the maximum growth-inhibitory effect. On the other hand, there was no synergy between butyrate and the drugs, or AN-9 and anti-metabolic agents in inhibiting the growth of the cells, suggesting that the synergistic effect is specific to AN-9 and DNA-reacting agents. AN-9 as a single agent prolonged the survival of mice inoculated with Mm-A cells in a dose-dependent manner. Moreover, administration of AN-9 plus daunorubicin (DNR) markedly prolonged their survival. These results suggest that combination with AN-9 and DNR entails an obvious therapeutic potential.
 ...
PMID:An anti-cancer derivative of butyric acid (pivalyloxmethyl buterate) and daunorubicin cooperatively prolong survival of mice inoculated with monocytic leukaemia cells. 906 6

Butyric acid (BA) was shown to induce hemoglobinization of K562 cells in a dose- and time-dependent manner. The maximal differentiation (54% of hemoglobinized cells) was obtained with the 0.5 mM concentration, which induced a 60% inhibition of cell growth at day 3 without cytotoxicity. Parallel to the kinetics of hemoglobinization, a rapid increase in gamma-globin and porphobilinogen deaminase (PBGD) mRNAs was observed in BA-treated cells. This increase was time-dependent and higher for gamma-globin than for PBGD (six- and two-fold at day 3, respectively). In contrast, erythropoietin receptor mRNAs were not affected by BA treatment. Analysis of erythroid transcription factor mRNA levels during the time course of BA treatment showed, for the first time, an early and marked (up to three-fold) increase in p45 NF-E2 mRNA, contrasting with that of GATA-1 mRNA (<1.5-fold). Taken together, these results showed the rapid differentiating effect of BA and suggest the involvement of the NF-E2 transcription factor.
Leukemia 1997 Sep
PMID:Time-course of butyric acid-induced differentiation in human K562 leukemic cell line: rapid increase in gamma-globin, porphobilinogen deaminase and NF-E2 mRNA levels. 930 15

Downregulation of bcr-abl expression in the chronic myelogenous leukemia cell line K562 using antisense oligonucleotides has been shown to enhance the sensitivity of the cells to apoptotic stimuli, suggesting that p210 bcr-abl, like bcl-2 functions as an anti-apoptosis factor (McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhibition of p210 bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a butyric acid analog, arginine butyrate, was capable of inducing apoptosis in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To further explore the mechanisms of this effect, we examined expression of p210 bcr-abl after butyrate exposure and found a dose-related inhibition of p210 bcr-abl protein without concordant change in other phosphoproteins, including the JAK-1 kinase. Further analysis revealed that the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results suggest that arginine butyrate and other butyrate analogs alone or in combination may be useful in the therapy of patients with chronic myelogenous leukemia or bcr-abl expressing acute leukemias.
Leukemia 1998 Jun
PMID:Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells. 963 22

The aromatic fatty acid phenylbutyrate (PB) induces cytostasis, differentiation, and apoptosis in primary myeloid leukemic cells at clinically achievable concentrations. In the present study, we have investigated the structural and cellular basis for PB-induced cytostasis, using the ML-1 human myeloid leukemia cell line as a model system. PB induced a dose-dependent increase in cells in G1 with a corresponding decrease in cells in S-phase of the cell cycle. At comparable doses, PB induced expression of CD11b, indicating myeloid differentiation. At higher doses, the drug induced apoptosis. The antitumor activity was independent of the aromatic ring, as butyric acid (BA) was of equal or greater potency at producing these biological changes. In contrast, shortening of the fatty acid carbon chain length, as demonstrated with phenylacetate (PA), significantly diminished drug potency. Consistent with their effects on cell cycle, PB and BA, but not PA, induced the cyclin-dependent kinase inhibitor, p21(WAF1/CIP1), and led to the appearance of hypophosphorylated Rb, suggesting a role for p21(WAF1/CIP1) in PB-induced cytostasis. Therefore, it appears that the fatty acid moiety of PB, rather than its aromatic ring, is critical for its activity in myeloid leukemic cells. These data provide a potential mechanistic basis for the increased potency of PB over PA previously demonstrated in primary leukemic samples, and support the further clinical development of PB in the treatment of hematologic malignancies.
Leukemia 1999 Aug
PMID:Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis. 1045 Jul 53

A group of 3'-O-butanoyl, 5'-O-butanoyl, and 3',5'-di-O-butanoyl esters of 5-fluoro-2'-deoxyuridine (FDU), and 2',5-difluoro-2'-deoxyuridine (DFDU), 3'-O-retinoyl, and 3',5'-di-O-retinoyl esters of FDU, and 5'-O-bis(2,2,2-trichloroethyl)phosphoryl-FDU and its 3'-O-butanoyl ester, was synthesized. These compounds were designed to act as double prodrugs that would serve as a depot to release two active drugs that act through different mechanisms. Thus, a nucleotide derivative of FDU or DFDU could act as a competitive inhibitor for thymidylate synthase, whereas retinoic acid and butyric acid would be expected to induce cell differentiation. The in vitro anticancer activities for these prodrugs were determined against a panel of nine tumor types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, breast) that encompassed about 60 human tumor cell lines. Structure-activity relationships indicate that O-butanoyl esters of FDU are approximately equipotent to FDU, the O-butanoyl esters of DFDU are less active than FDU, and the retinoyl and bis(2,2,2-trichloroethyl)phosphate derivatives of FDU exhibit comparable activity to FDU. In addition to their cytotoxic effect, 3'-O-retinoyl-FDU (12) and 3'-O-butanoyl-5'-O-bis(2,2,2-trichloroethyl)phosphoryl-FD U (16) also induced in vitro cell differentiation of promyelocytic leukemia HL60 cells. These combined cytotoxic and cell differentiation effects exhibited by 12 and 16 produced greater morphological drug-induced granulation and neutrophil vacuolation, and more cell apoptosis, than observed upon exposure to either retinoic acid or sodium butanoate. Dose-escalation studies in mice showed that 12 or 16 did not induce any acute or chronic toxicity, change in plasma clinical chemistry parameters, or gross histapathological changes at 60 days following an initial dosage regimen of 0.013 mmol/kg i.p. for 7-consecutive days. The in vivo growth delay response of murine mammary EMT6 solid tumors suggests that 3'-O-retinoyl-FDU (12) delays tumor growth relative to the other prodrugs investigated, sodium butyrate, retinoic acid, FDU, or a combination of retinoic acid and FDU. These preliminary results suggest that 3'-O-retinoyl-FDU (12) warrants further in vivo investigation to determine its tissue biodistribution and pharmacokinetic parameters that would be of value in assessing its potential usefulness as an anticancer prodrug.
 ...
PMID:Synthesis and biological evaluation of butanoate, retinoate, and bis(2,2,2-trichloroethyl)phosphate derivatives of 5-fluoro-2'-deoxyuridine and 2',5-difluoro-2'-deoxyuridine as potential dual action anticancer prodrugs. 1048 39

Butyrate induces cytodifferentiation in many tumor cells of different origin, suggesting that an as yet unidentified common mechanism inherent to malignant cells is the target of butyrate action. This study determined the role of different mitogen-activated protein (MAP) kinase signal transduction pathways in butyrate-induced erythroid differentiation of K562 human leukemia cells. Using a panel of anti-ERK, JNK, and p38 phosphospecific antibodies, the study showed that phosphorylation of ERK and JNK is decreased following treatment of cells with butyrate, whereas phosphorylation of p38 is increased. In contrast, a K562 subline defective in butyrate-mediated induction of erythroid differentiation did not reveal these changes in phosphorylation patterns. Inhibition of ERK activity by UO126 induces erythroid differentiation and acts synergistically with butyrate on hemoglobin synthesis and inhibition of cell proliferation, whereas inhibition of p38 activity by SB203580 completely abolished induction of hemoglobin expression by butyrate. Taken together, our data suggest a model in which butyrate induces erythroid differentiation of K562 cells by inhibition of ERK and activation of p38 signal transduction pathways.
 ...
PMID:Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways. 1073 12

Folates have been co-administered with some antifolates to diminish host toxicity; however, the extent to which this will reduce antitumor activity is not known. To further clarify this issue, studies were undertaken to characterize and quantitate the impact of alterations in intracellular folate levels on the activities of a variety of antifolates in L1210 murine leukemia cells. Intracellular folate cofactor levels increased almost in proportion to the increase in extracellular 5-formyltetrahydrofolate (5-CHO-THF) over a concentration range that encompassed physiological levels of 5-methyltetrahydrofolate. This resulted in a spectrum of increases in the ic50 values of antifolates upon continuous exposure to drugs [Lometrexol (DDATHF) (70x) > trimetrexate (TMQ) (30x), multitargeted antifolate, LY231514 (ALIMTA) (30x) > Raltitrexed, Tomudex (ZD1694) (10x), 6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid (LY309887) (10x) > methotrexate (MTX) (6x) > (2S)-2-[o-fluoro-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamido]-4-(tetrazol-5-yl) butyric acid (ZD9331) (3x), N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-l-ornithine (PT523) (3x)]. Upon a 4-hr pulse exposure to drug, the ic50 values for DDATHF and ALIMTA were increased > 180- and 5-fold, respectively, with only a 2.5-fold increase in the extracellular 5-CHO-THF level within the physiological range. The reductions in drug sensitivities could be attributed to decreases in accumulation of polyglutamate derivatives of ALIMTA and DDATHF. Hence, in these studies, natural folates diminished the activity of agents that undergo polyglutamation by suppression of the formation of these active congeners at the level of folylpolyglutamate synthetase. For inhibitors of dihydrofolate reductase, the suppressive effect of endogenous folates appears to be due to competition between the antifolate and dihydrofolate at the level of the target enzyme. These data should be carefully considered in the design of regimens with antifolates, which incorporate co-administration of folates.
 ...
PMID:Marked suppression of the activity of some, but not all, antifolate compounds by augmentation of folate cofactor pools within tumor cells. 1127 72

A previous report [Virus Genes 6 (1992) 365-378] has shown that the US1 gene of Marek's disease virus serotype 1 (MDV1) encodes a homologue of herpes simplex virus type 1 infected cell protein No. 22 (ICP22). In the present study, we expressed and identified a product of the MDV1 US1 gene in chicken embryo fibroblasts (CEFs) with the aid of a recombinant baculovirus expressing a Flag epitope-tagged MDV1 US1 gene, under control of the SRalpha promoter (composed of the enhancer region of the simian virus 40 early promoter and the R region of the human T-cell leukaemia virus type 1 long terminal repeat). In CEF infected with the recombinant baculovirus, MDV1 ICP22 was specifically and efficiently expressed in the presence of n-butyric acid. The apparent M(r) of the expressed protein was 30,000. Reporter gene assays revealed that MDV1 ICP22 by itself transactivated an MDV1 ICP27 promoter/reporter construct weakly but specifically, and furthermore, worked synergistically with MDV1 ICP4 to efficiently up-regulate the MDV1 ICP27 promoter. MDV1 ICP22 may be a regulatory protein that stimulates viral promoters in co-operation with other viral regulatory proteins such as MDV1 ICP4.
 ...
PMID:Identification and characterization of Marek's disease virus serotype 1 (MDV1) ICP22 gene product: MDV1 ICP22 transactivates the MDV1 ICP27 promoter synergistically with MDV1 ICP4. 1185 80


<< Previous 1 2 3 4 Next >>