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)

The influence of the diterpene, forskolin, was studied on adenylate cyclase activity in membranes of rat basophilic leukemia cells. Forskolin increased basal adenylate cyclase activity maximally 2-fold at 100 microM. However, adenylate cyclase activity stimulated via the stimulatory guanine nucleotide-binding protein, Ns, by fluoride and the stable GTP analog, guanosine 5'-O-(3-thiotriphosphate), was inhibited by forskolin. Half-maximal and maximal inhibition occurred at about 1 and 10 microM forskolin, respectively. The inhibition occurred without an apparent lag phase, whereas the enzyme stimulation by forskolin was preceded by a considerable lag period. The inhibition was not affected by treating intact cells or membranes with pertussis toxin and proteolytic enzymes, respectively, which have been shown in other cell types to prevent adenylate cyclase inhibition mediated by the guanine nucleotide-binding regulatory component, Ni. The forskolin inhibition of the stable GTP analog-activated adenylate cyclase was impaired by increasing the Mg2+ concentration and was reversed into a stimulation by Mn2+. Under optimal inhibitory conditions, forskolin even decreased basal adenylate cyclase activity. Finally, forskolin largely reduced the apparent affinity of the rat basophilic leukemia cell adenylate cyclase for its substrate, MgATP, which reduction resulted in an apparent inhibition at low MgATP concentrations and a loss of the inhibition at higher MgATP concentrations. The data indicate that forskolin can cause both stimulation and inhibition of adenylate cyclase and, furthermore, they suggest that the inhibition may not be mediated by the Ni protein, but may be caused by a direct action of forskolin at the adenylate cyclase catalytic moiety.
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PMID:Stimulation and inhibition of rat basophilic leukemia cell adenylate cyclase by forskolin. 389 83

Methotrexate (MTX) blocks the de novo synthesis of purines and pyrimidines due to a diminution of reduced folates, and produces an accumulation of intracellular 5-phosphoribosyl-1-pyrophosphate (PRPP). Phosphoribosyltransferases, in the presence of PRPP, synthesize nucleotides starting on purine bases, that are activated to triphosphates ("rescue pathway"). The authors study the activity of the rescue pathways in L1210 leukemia cells in vitro to restore the levels of ATP and GTP that have been lowered by MTX. Hypoxanthine (Hpx) was used as a preformed source of purines, high efficiency liquid chromatography was employed to estimate the intracellular concentrations of ATP and GTP. Two hours after 0.1 mM Hpx addition to in vitro L1210 cells in the presence of 0.1 microM MTX, the amount of ATP and GTP increased 5 to 7 times. In former experiments the author has shown that the uptake of PRPP increases when Hpx is added to L1210 cells exposed to MTX. The results of this work show that L1210 leukemia cells in vitro can use the rescue pathways of purine synthesis when Hpx is present in the growth medium, so preventing the anti-purine effect of MTX.
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PMID:[Use of purine rescue pathways by L1210 cells exposed to methotrexate in vitro]. 608 40

The Mn2+-dependent endonuclease activity associated with the avian myeloblastosis virus RNA-directed DNA polymerase has been shown to be activated by ATP in the presence of Mg2+. In the presence of Mn2+ the endonucleolytic activity was stimulated about 3-fold by the addition of ATP. The earlier identified Mr = 40,000 Friend murine leukemia virus (F-MuLV)-associated endonuclease which functions in the presence of both Mg2+ and Mn2+ has also been shown to be similarly stimulated by ATP. For both endonuclease activities stimulation was only observed at ATP concentrations above 0.5 mM, and it did not increase upon elevating the ATP concentration above 2.5 mM. ADP and dATP also stimulated both activities, although not to the same extent as ATP. GTP had no apparent effect and AMP seemed to inhibit both activities. The effect ATP analogs had on the F-MuLV associated endonuclease activity could suggest that the endonuclease reaction in the presence of ATP might involve the cleavage of beta-gamma phosphate bonds in ATP. Neither adenyl-5'-yl imidodiphosphate nor (beta, gamma-methylene)adenosine 5'-triphosphate stimulated the activity, whereas significant stimulation was observed in the presence of (alpha, beta-methylene)adenosine 5'-triphosphate. Although no ATPase activity could be detected in the purified F-MuLV endonuclease preparation, the data do not exclude the possibility that ATP may be cleaved in amounts which are equivalent to the number of nicks introduced into DNA by the virus-associated endonuclease. In the presence of ATP and Mg2+ the F-MuLV-associated endonuclease nicked both supercoiled and linear DNA duplexes extensively, although the former was nicked more readily than the latter. Single-stranded DNA functioned poorly as a substrate. The nicks introduced by the enzyme contained a 5'-phosphoryl terminus and a 3'-hydroxyl group.
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PMID:Effect of ATP on the Friend Murine leukemia virus-associated endonuclease activity and the endonuclease activity of the avian myeloblastosis virus RNA-directed DNA polymerase. 616 71

The effect of 3-deazauridine (DAUR) on the intracellular purine and pyrimidine nucleotide pools and on the metabolism of azacitidine (aza-CR) in L1210 cells, sensitive (L1210/0) and resistant (L1210/ara-C) to cytarabine (ara-C), was examined. The consequences of such a modulation were correlated with the therapeutic efficacy of this combination in mice bearing L1210 leukemia. In vitro and in vivo treatment of both L1210 sublines with DAUR produced a dose- and time-dependent reduction in the CTP and dCTP pools and an increase in the UTP pool. In addition to these changes in the pyrimidine nucleotide pools, DAUR produced a modest increase in the GTP pool and a marked expansion of the ATP pool in L1210/ara-C 12 hrs following in vivo drug treatment. These perturbations in nucleoside triphosphate pools were more pronounced in L1210/ara-C cells. Treatment of mice bearing L1210/ara-C with 100 mg/kg of DAUR reduced the CTP and dCTP pools in the leukemic cells by greater than 90% within 1-3 hrs after administration of the drug, with complete recovery of these pools occurring within 12 hrs. Fluctuation of the pyrimidine nucleoside pools after DAUR treatment was correlated with the subsequent increase in aza-CR metabolism and its incorporation into RNA and with the potentiation of the in vivo toxicity of aza-CR. In mice bearing L1210/0 or L1210/ara-C tumors, DAUR or aza-CR produced a less than or equal to 23% increase in life-span (ILS). Administration of aza-CR 3 hrs after DAUR, however, produced about an 80% ILS among mice bearing L1210/ara-C tumors, but no more than an approximately 20% ILS among mice bearing L1210/0 tumors. These data suggest that the therapeutic activity of the sequential combination of DAUR and aza-CR against mice bearing L1210/ara-C cannot be explained, per se, on the basis of the initial intracellular modulation of nucleotide pools, since DAUR affected these pools of the two tumors to approximately the same degree. What appears to be important, however, is that such a modulation by DAUR preferentially affected the metabolism of aza-CR in leukemic cells resistant to ara-C which are devoid of deoxycytidine kinase activity.
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PMID:Effect of 3-deazauridine on the metabolism, toxicity, and antitumor activity of azacitidine in mice bearing L1210 leukemia sensitive and resistant to cytarabine. 619 May 58

We report the purification to homogeneity of a 20,000-dalton, transformation-related, rat cell membrane protein. This protein, p20, was originally identified in preparations of a defective woolly monkey leukemia virus pseudotype of Kirsten sarcoma virus. The chromatographically purified p20 was an acidic hydrophobic protein, capable of specifically binding GTP (dissociation constant = 15 microM). This nucleotide binding property and other previously reported characteristics were similar to properties ascribed to the Harvey sarcoma virus src gene product. p20 also appeared similar to this src gene product when immunoprecipitates of both proteins were directly compared by one- and two-dimensional NaDodSO4 gel electrophoreses. However, the proteins were not identical, because their tryptic maps differed. Using a competition radioimmunoassay, we have measured the concentration of p20 in cells, viruses, and rat tissues: p20 was not encoded by rat sarcoma viruses because it was increased only slightly after Kirsten sarcoma virus transformation of rat cells and was not increased in nonrat cells transformed by the Kirsten or Harvey sarcoma virus. Remarkably, of 10 rat tissues examined, p20 was found predominantly in brain, specifically in the membranes.
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PMID:A brain membrane protein similar to the rat src gene product. 626 48

An endonuclease activity associated with purified proteinase K-treated intracisternal A-particles was identified and characterized. The activity required divalent cations, preferring Mn2+ to Mg2+. Salt concentrations above 50 mM inhibited the activity. The endonuclease was greatly stimulated by ATP, ADP, and dATP, whereas AMP appeared to produce a slight inhibition. GTP had no apparent effect on the activity. The enzyme introduced single-stranded nicks into DNA and nicked preferentially supercoiled DNA duplexes in the presence of ATP, although linear duplexes also functioned as substrates. Single-stranded DNA was not nicked to any great extent. The molecular weight of the enzyme was estimated to be about 40,000. The characteristics of this enzyme are very similar to those of the endonuclease found associated with Friend murine leukemia virus.
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PMID:Properties of an intracisternal A-particle-associated endonuclease activity which is stimulated by ATP. 627 25

1-beta-D-Ribofuranosyl-4-methylthiopyrazolo(3,4-d)pyrimidine (I) has been converted into its 5'-monophosphate (III) by reacting with POCl3 in trialkyl phosphates or by phosphorylating 2',3'-O-ethoxymethylidene derivative of riboside (I) using 2-cyanoethyl phosphate in the presence of DCC and subsequent removal of blocking groups. Condensation of nucleotide (III) imidazolide with pyrophosphoric acid afforded corresponding 5'-triphosphate. Pools of natural NTPs and riboside (I) phosphates were monitored by HPLC after administering riboside (I), phosphate (III), or 4-methylthiopyrazolo(3,4-d)pyrimidine (II) into mice with leukemia L1210 or after incubating CaOv culture cells with these compounds. Treatment with riboside (I) or nucleotide (III) possessing antileukemic and cytotoxic activites led to much higher level of monophosphate (III), than treatment with biologically inactive base (II). ATP and GTP levels in CaOv cells incubated with (I) or (III) decreased by 60-70%, whereas (II) did not affect NTP pool. Bioactivation of nucleoside (I) into monophosphate (III) proceeds via direct phosphorylation by adenosine kinase. No tranformation of (II) into (I) or (III) occurs under these conditions.
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PMID:[Biotransformation of 1-beta-D-ribofuranosyl-4-methylthiopyrazolo(3,4-d)pyrimidine and its 5'-monophosphate]. 649 15

In a previous report we demonstrated in mouse lymphoma (S-49) cells that DNA synthesis inhibition resulting from guanine starvation is associated with GTP rather than dGTP depletion. Since several effective anticancer drugs act via guanine depletion, it is important to test whether critical GTP depletion is unique to S-49 cells or also occurs in other cell lines. Mycophenolic acid-induced guanine starvation caused a drastic DNA synthesis inhibition in the human lymphoblastic T leukemia (CEM) and the mouse B leukemia (L1210) cell lines, which was again associated with GTP depletion rather than dGTP depletion. These results suggest that GTP depletion represents a common target of purine antimetabolites in mammalian cells.
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PMID:Guanine ribonucleotide depletion in mammalian cells. A target of purine antimetabolites. 657 81

We studied the ability of 2'-deoxyguanosine (dGuo) to influence 1-beta-D-arabinofuranosylcytosine (ara-C) inhibition of soft agar cloning of the cultured human leukemia cell line K562. Ara-C alone inhibited cloning in concentrations of greater than 10 nM, with a steep drop in colony formation observed between 10 and 100 nM. dGuo and ara-C synergistically inhibited cloning; the combination of ineffective concentrations of dGuo (10-50 microM) and ara-C (less than or equal to nM) inhibited cloning by 40-70%. In K562 cells, dGuo is metabolized by both nucleoside kinase and purine nucleoside phosphorylase (PNP), resulting in augmentation of both the GTP pool (to more than 200% of control after a 3 hr incubation with 500 microM dGuo) and the dGTP pool (to more than 2700% of control after 3 hr with 500 microM dGuo). dGuo (50-500 microM) caused a decrease in the dCTP and dTTP pools and an increase in the dATP pool. Synergistic concentrations of dGuo plus 10 nM ara-C augmented the ara-CTP pool up to 800% of control after 3 hr to levels equivalent to those observed after incubation with 500 nM ara-C alone. Incorporation of 10 nM ara-CTP into DNA also increased in the presence of dGuo (up to a maximum of 300% of control), but only to a level that approximated the value observed with nM ara-C alone. The disparity between enlargement of the ara-CTP pool and augmentation of ara-C incorporation into DNA is consistent with the observation of Steinberg et al. [Cancer Res. 39, 4330 (1979)] that high concentrations of dGTP may inhibit DNA polymerase activity. Thus, synergy between dGuo and ara-C is multifactorial, possibly involving inhibition of DNA polymerase by elevated dGTP and ara-CTP pools and augmented incorporation of ara-C into DNA.
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PMID:Synergistic inhibition of human leukemia cell growth by deoxyguanosine and 1-beta-D-arabinofuranosylcytosine. 671 15

Alteration of purine metabolism using adenine was studied in mouse L1210 leukemia cells for its effect on dThd-mediated inhibition of growth and deoxyribonucleotide pool perturbations. Inhibition of cell growth caused by 10 to 50 microM dThd was enhanced more than additively by 100 microM adenine which was only slightly inhibitory when administered alone. Adenine at 100 microM affected ribonucleotide levels by expanding the ATP pool and causing slight decreases in the GTP, UTP and CTP pools, while dThd alone or in combination with adenine had no effect on ribonucleotide pools. dThd at 10 microM caused a more than 2-fold increase in the dTTP pool and a marked but transient decrease in the dCTP pool with lesser effects on purine deoxyribonucleotide levels. Adenine at 100 microM produced only slight, transient increase in the dATP pool. Exposure of cells to dThd plus adenine compared with individual agents produced more than additive increases in dTTP and dATP pools. The decrease in the dCTP level was more with combined agents than with dThd alone. The results showed that an alteration in adenine nucleotide pools modifies the activity of dThd through greater enhancement of dTTP levels leading to a greater suppression of the dCTP pool.
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PMID:Purine modulation of thymidine activity in L1210 leukemia cells in vitro. 714 28


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