| 1. |
- Zhenchuk, Anna, et al.
(författare)
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Commentary: Mechanisms of anti-cancer action and pharmacology of clofarabine : in BIOCHEMICAL PHARMACOLOGY, ISSN 0006-2952, vol 78, issue 11, pp 1351-1359
- 2009
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 78:11, s. 1351-1359
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Clofarabine, a next-generation deoxyadenosine analogue, was developed on the basis of experience with cladribine and fludarabine in order to achieve higher efficacy and avoid extramedullary toxicity. During the past decade this is the only drug granted approval for treatment of pediatric acute leukemia. Recent clinical studies have established the efficacy of clofarabine in treating malignancies with a poor prognosis, such as adult, elderly, and relapsed pediatric leukemia. The mechanisms of its anti-cancer activity involve a combination of direct inhibition of DNA synthesis and ribonucleotide reductase and induction of apoptosis. Due to this broad cytotoxicity, this drug is effective against various subtypes of leukemia and is currently being tested as an oral formulation and for combination therapy of both leukemias and solid tumors. In this review we summarize current knowledge pertaining to the molecular mechanisms of action and pharmacological properties of clofarabine, as well as clinical experiences with this drug with the purpose of facilitating the evaluation of its efficacy and the development of future therapies.
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| 2. |
- Ekholm, Dag, et al.
(författare)
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Cyclic nucleotide phosphodiesterases (PDE) 3 and 4 in normal, malignant, and HTLV-I transformed human lymphocytes
- 1999
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Ingår i: Biochemical Pharmacology. - 0006-2952. ; 58:6, s. 935-950
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Tidskriftsartikel (refereegranskat)abstract
- Intracellular cyclic AMP, determined in part by cyclic nucleotide phosphodiesterases (PDEs), regulates proliferation and immune functions in lymphoid cells. Total PDE, PDE3, and PDE4 activities were measured in phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMC-PHA), normal natural killer (NK) cells, Jurkat and Kit225-K6 leukemic T-cells, T-cell lines transformed with human T-lymphotropic virus (HTLV)-I (a retrovirus that causes adult T-cell leukemia/lymphoma) and HTLV-II (a nonpathogenic retrovirus), normal B-cells, and B-cells transformed with Epstein-Barr virus (EBV). All cells exhibited PDE3 and PDE4 activities but in different proportions. In EBV-transformed B cells, PDE4 was much higher than PDE3. HTLV-I+ T-cells differed significantly from other T-lymphocyte-derived cells in also having a higher proportion of PDE4 activities, which apparently were not related to selective induction of any one PDE4 mRNA (judged by reverse transcription-polymerase chain reaction) or expression of the HTLV-I regulatory protein Tax. In MJ cells (an HTLV-I+ T-cell line), Jurkat cells, and PBMC-PHA cells, the tyrosine kinase inhibitor herbimycin A strongly inhibited PDE activity. Growth of MJ cells was inhibited by herbimycin A and a protein kinase C (PKC) inhibitor, and was arrested in G1 by rolipram, a specific PDE4 inhibitor. Proliferation of several HTLV-I+ T-cell lines, PBMC-PHA, and Jurkat cells was inhibited differentially by forskolin (which activates adenylyl cyclase), the selective PDE inhibitors cilostamide and rolipram, and the nonselective PDE inhibitors pentoxifylline and isobutyl methylxanthine. These results suggest that PDE4 isoforms may be functionally up-regulated in HTLV-I+ T-cells and may contribute to the virus-induced proliferation, and that PDEs could be therapeutic targets in immune/inflammatory and neoplastic diseases.
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| 3. |
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| 4. |
- Jonsson, Gösta, et al.
(författare)
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6-Hydroxydopamine induced degeneration of noradrenaline neurons in the scorbutic guinea-pig
- 1974
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952. ; 23:18, s. 2585-2593
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Tidskriftsartikel (refereegranskat)abstract
- The effect of the neurotoxic compound 6-hydroxydopamine and its immediate precursor 6-hydroxy-DOPA on noradrenaline uptake and storage in central and peripheral catecholamine neurons of scorbutic and normal guinea-pigs has been investigated. Endogenous noradrenaline in heart and brain as well as the in vitro uptake-accumulation of 3H-noradrenaline in iris and slices of heart and brain were not significantly changed in scorbutic animals. The in vitro formation of 3H-noradrenaline from 3H-dopamine was markedly reduced in heart slices of scorbutic guinea-pigs, due to ascorbic acid being a co-factor for dopamine-β-hydroxylase. There was an increased depletion of brain noradrenaline following tyrosine hydroxylase inhibition produced by α-methyl-p-tyrosine methylester in scorbutic animals, indicating an increased NA turnover. Administration of 6-hydroxydopamine or 6-hydroxy-DOPA resulted in a similar reduction of endogenous NA in brain and heart as well as of the in vitro uptake of 3H-noradrenaline in iris, and slices from heart, cerebral cortex and hypothalamus in scorbutic and control guinea-pigs. These results are discussed in view of current hypotheses on mechanisms involved in the neurotoxic action of 6-hydroxydopamine on catecholamine neurons.
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| 5. |
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| 6. |
- Kull, B, et al.
(författare)
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Differences in the order of potency for agonists but not antagonists at human and rat adenosine A2A receptors
- 1999
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Ingår i: Biochemical Pharmacology. - 0006-2952. ; 57:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- To examine possible species differences in pharmacology, rat adenosine A2A receptors were studied in PC12 (pheochromocytoma) cells, and human receptors in Chinese hamster ovary (CHO) cells transfected with the cloned human A2A receptor cDNA. Using [3H]-5-amino-7(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine ([3H]-SCH 58261) as radioligand, the estimated Bmax (maximal binding) was 538 and 2085 fmol/mg in CHO and PC12 cells, respectively. The Kd (dissociation constant) values for [3H]-SCH 58261 were 1.05 and 5.6 nM in the two cell types, respectively. The order of potency of antagonists and most agonists was the same in both cell types, but 2-phenylaminoadenosine and 2-chloroadenosine were relatively less potent in PC12 cells than in CHO cells. In the functional assay, using cyclic AMP accumulation, all agonists tested were more potent in CHO than in PC12 cells, but this could not be readily explained by differences in adenylyl cyclase or in the expression of G proteins. As in the case of binding, the relative agonist potencies were similar for most compounds, but 2-phenylaminoadenosine and 2-chloroadenosine were more potent at human A2A receptors in CHO cells than predicted from the data obtained on rat A2A receptors in PC12 cells. Antagonists were approximately equipotent in the two cells. These results show that, despite only small differences in amino acid sequences and no difference in antagonist pharmacology, the relative order of potency of receptor agonists can differ between species homologues of the adenosine A2A receptor.
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| 7. |
- Kull, B, et al.
(författare)
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Reciprocal interactions between adenosine A2A and dopamine D2 receptors in Chinese hamster ovary cells co-transfected with the two receptors
- 1999
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Ingår i: Biochemical Pharmacology. - 0006-2952. ; 58:6, s. 1035-1045
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Tidskriftsartikel (refereegranskat)abstract
- Human adenosine A2A and rat dopamine D2 receptors (A2A and D2 receptors) were co-transfected in Chinese hamster ovary (CHO) cells to study the interactions between two receptors that are co-localized in striatopallidal gamma-aminobutyric acid-(GABA)ergic neurons. Membranes from transfected cells showed a high density of D2 (3.6 pmol per mg protein) and A2A receptors (0.56 pmol per mg protein). The D2 receptors were functional: an agonist, quinpirole, could stimulate GTPgammaS binding and reduce stimulated adenylyl cyclase activity. The A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) decreased high-affinity binding of the agonist dopamine at D2 receptors. Activation of adenosine A2A receptors shifted the dose-response curve for quinpirole on adenosine 3',5'-cyclic monophosphate (cAMP) to the right. However, CGS 21680 did not affect dopamine D2 receptor-induced GTPgammaS binding, but did cause a concentration-dependent increase in cAMP accumulation. The maximal cAMP response was decreased by the D2 agonist quinpirole in a concentration-dependent manner, but there was no change in EC50 and no effect in cells transfected only with adenosine A2A receptors. A2A receptor activation also increased phosphorylation of cAMP response element-binding protein and expression of c-fos mRNA. These effects were also strongly counteracted by quinpirole. These results show that the antagonistic actions between adenosine A2A and dopamine D2 receptors noted previously in vivo can also be observed in CHO cells where the two receptors are co-transfected. Thus, no brain cell-specific factors are required for such interactions. Furthermore, the interaction at the second messenger level and beyond may be quantitatively more important than A2A receptor-mediated inhibition of high affinity D2 agonist binding to the receptor.
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| 8. |
- Larsson, Christer, et al.
(författare)
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Ethanol inhibits the peak of muscarinic receptor-stimulated formation of inositol 1,4,5-trisphosphate in neuroblastoma SH-SY5Y cells
- 1995
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952. ; 50:5, s. 647-654
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Tidskriftsartikel (refereegranskat)abstract
- The effect of ethanol on muscarinic receptor-stimulated formation of inositol 1,4,5-trisphosphate was studied in human neuroblastoma SH-SY5Y cells. Stimulation with carbachol induced a biphasic increase of inositol 1,4,5-triphosphate with an initial peak after 10 sec declining to a plateau phase of elevation above basal levels, which was sustained for at least 5 min in the presence of agonist. The peak, but not the plateau phase, was concentration-dependently decreased by exposure to ethanol. Maximal inhibition was obtained within 30 sec of exposure to ethanol. Ethanol caused an increase in the EC50 value of carbachol for the initial rate of inositol 1,4,5-trisphosphate formation, measured after 10 sec of stimulation, from 98 microM in the absence to 196 microM in the presence of 100 mM ethanol. The potencies of pirenzepine and hexahydro-sila-difenidol hydrochloride for inhibiting [3H]quinuclidinyl benzilate binding and inositol 1,4,5-trisphosphate formation suggest that both phases are mediated via the muscarinic M1 receptor. Phorbol 12-myristate 13-acetate inhibited both phases of inositol 1,4,5-trisphosphate formation, whereas okadaic acid and modulators of cAMP-dependent protein kinase were without any effect. There was no inhibitory effect of ethanol when protein kinase C was inhibited by H7 and calphostin C, indicating that the ethanol effect is dependent on protein kinase C activity.
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| 9. |
- Salazar, G, et al.
(författare)
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Apoptosis in male germ cells in response to cyclin A1-deficiency and cell cycle arrest
- 2003
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Ingår i: Biochemical Pharmacology. - 0006-2952. ; 66:8, s. 1571-1579
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Tidskriftsartikel (refereegranskat)abstract
- Male mice homozygous for a mutated allele of the cyclin A 1 gene (Ccna 1) are sterile due to a block in cell cycle progression before the first meiotic division. Meiosis arrest in Ccna1(-1-) spermatocytes is associated with desynapsis abnormalities, lowered MPF activity, and apoptosis as evidenced by TUNEL-positive staining. With time, adult testicular tubules exhibit severe degeneration: some tubules in the older animals are almost devoid of germ cells at various stages of spermatogenesis. The mechanisms by which the cells sense the cell cycle arrest and the regulation of the decision to undergo cell death are under investigation. (C) 2003 Elsevier Inc. All rights reserved.
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| 10. |
- Simonsson, Per, et al.
(författare)
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Ethanol potentiates serotonin stimulated inositol lipid metabolism in primary astroglial cell cultures
- 1989
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952. ; 38:17, s. 2801-2805
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Tidskriftsartikel (refereegranskat)abstract
- Serotonin-stimulated activation of phospholipase C in primary astroglial cell cultures was studied as a mean of evaluating the effect of acute ethanol exposition on this signal transduction system. The addition of 50-150 mM ethanol prior to stimulation with 10(-5) M serotonin led to a potentiation of the serotonin-induced [3H]-inositol phosphate formation and an increased incorporation of [3H]-inositol into the three phosphoinositides studied. This potentiating effect of ethanol was observed only when ethanol was added together with serotonin. No stimulatory effect of ethanol per se was found. Furthermore, ethanol had no effect on arginine-vasopressin, bradykinin or phenylephrine stimulated inositol lipid metabolism.
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