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)

Wild-type (clone 707) Friend murine leukaemia cells were compared with two ara-C-resistant subclones in terms of sensitivity to cell killing and mutagenesis to 6-thioguanine resistance following treatment with ethyl methane sulphonate, methyl methane sulphonate and UV irradiation. The ara-C-resistant subclones, 707DKE and 707DK48, had respective deoxycytidine kinase activities of 6.7 and 5.4% the values found in wild-type cells. No clear pattern of altered sensitivity to cell killing or mutagenesis emerged between the wild-type cells and the ara-C-resistant subclones. These results do not provide evidence for a role of deoxycytidine kinase in determining sensitivity to mutagenic agents in the Friend cell line.
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PMID:Cell killing and mutagenesis by alkylating agents and UV irradiation in wild-type and deoxycytidine-kinase-deficient Friend murine leukaemia cells. 328 38

2',2'-Difluorodeoxycytidine (dFdC) is a new deoxycytidine analogue with good activity against human leukemic cell lines and murine solid tumors, while the activity of 1-beta-D-arabinofuranosylcytosine (ara-C) is established in experimental systems and for the treatment of human adult leukemia. This study compared the cellular metabolism and cytotoxic properties of dFdC and ara-C in Chinese hamster ovary cells. In wild-type cells, dFdC was significantly more cytotoxic than ara-C after both 4- and 18-h incubations. The 5'-triphosphate of dFdC (dFdCTP) was the major cellular metabolite (85-90%), reaching cellular concentrations up to 20-fold greater than those observed for ara-C 5'-triphosphate at equimolar concentrations of the parent drug. A deoxycytidine kinase-deficient mutant neither accumulated dFdCTP nor showed any cytotoxic response up to drug concentrations of 100 microM. The cytotoxicity of dFdC could be competitively reversed by deoxycytidine further suggesting that dFdC, like ara-C, required phosphorylation by deoxycytidine kinase for biological activity. Several explanations for the different cellular accumulation of the drug triphosphates were established: (a) nucleoside transport studies demonstrated that the membrane permeation of dFdC was 65% more rapid than that of ara-C; (b) deoxycytidine kinase had a higher affinity for dFdC (Km = 3.6 microM) than for ara-C (Km = 8.8 microM), while the Km for deoxycytidine was 1.4 microM; (c) the elimination of intracellular dFdCTP was biphasic with t1/2 alpha = 3.9 and t1/2 beta greater than 16 h while the degradation of ara-CTP was monophasic and significantly faster (t1/2 = 0.7 h). The comparatively long half-life of dFdCTP was related to the prolonged inhibition of DNA synthesis after removal of exogenous nucleoside. Together these factors contribute to the more potent cytotoxicity of dFdC compared with ara-C.
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PMID:Comparison of the cellular pharmacokinetics and toxicity of 2',2'-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. 338 95

The in vivo development of an ara-C-resistant leukemic cell line is reported in a rat leukemia model (BNML) that is generally accepted as a relevant model for human acute myelocytic leukemia. It took 32 continuous leukemia transplant generations, performed over 20 months, and a total dose of 28.5 g ara-C/kg to induce complete resistance. Preliminary data indicate that the development of ara-C resistance is related with decreased intracellular levels of deoxycytidine kinase. Deoxycytidine deaminase levels were not increased. Thus this enzyme does not seem to be involved with induction of resistance. This preclinical rat model for human AML provides a solid basis for studies in depth on the mechanism(s) and possible prevention and effective treatment of resistance to ara-C.
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PMID:In vivo development of cytosine arabinoside resistance in the BN acute myelocytic leukemia. 347 77

The pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) and their respective 5'-triphosphates, ara-CTP and F-ara-ATP, were compared in human plasma and circulating leukemic blasts (CLB) since initial phosphorylation of ara-C and F-ara-A is catalyzed by the same enzyme, deoxycytidine kinase. These investigations were conducted in 4 patients after the first infusion of high-dose ara-C therapy (3 g/m2 i.v. infused over 2 hr) and, following the failure of each to respond, after the initial bolus of F-ara-A monophosphate (50-100 mg/m2 i.v. over 30 min) in a subsequent treatment regimen. The median terminal rate of elimination (t1/2) of F-ara-A was 8.4 hr compared to 2.2 hr for ara-C. The median t1/2 for F-ara-ATP in CLB was 12.2 hr relative to 1.9 hr for ara-CTP. To evaluate the possibility that diminished deoxycytidine kinase was a mechanism of drug resistance, the relative area under the concentration X time curve (AUC) of the active triphosphate of each prodrug in the CLB of individuals was compared. The intracellular nucleotide AUC was normalized by dividing it by the AUC of the respective nucleoside in plasma. A value of 1.0 for the resulting ratio would be expected if the accumulation and retention of F-ara-ATP and ara-CTP were identical. In these patients, however, this ratio ranged between 0.2 and 68.2. When a similar analysis was performed in vitro using four established human leukemia cell lines, a 150-fold variation was found in the normalized nucleotide AUC ratio. Thus, the metabolic characteristics of ara-CTP in CLB of patients who fail to respond to high-dose ara-C may not predict the cellular metabolism of F-ara-ATP in the same patient at a later disease stage.
Leukemia 1987 Sep
PMID:Comparison between the plasma and intracellular pharmacology of 1-beta-D-arabinofuranosylcytosine and 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate in patients with relapsed leukemia. 347 43

Pretreatment of L5178Y murine leukemia cells with uracil arabinoside (ara-U) enhances the cytotoxicity of cytosine arabinoside (ara-C). This effect is mediated by the cytostatic effect of ara-U, which causes a delay of cell progression through S-phase. Consequently, the specific activity of enzymes that peak during S-phase increases, and deoxycytidine kinase increases 3.6-fold over untreated controls. This allows enhanced anabolism of ara-C to nucleotides, as well as increased incorporation into DNA with ultimate synergistic cytotoxicity. It is postulated that the systemic metabolism of high-dose ara-C to sustained high levels of ara-U in patients with acute leukemia may enhance the activity of subsequent doses of ara-C, and thus contribute to a means for pharmacologic self-potentiation, contributing to the unique therapeutic activity of high-dose ara-C.
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PMID:Effect of uracil arabinoside on metabolism and cytotoxicity of cytosine arabinoside in L5178Y murine leukemia. 403 4

2-Chlorodeoxyadenosine (CdA), an adenosine-deaminase-resistant purine deoxynucleoside, is markedly toxic toward human T-lymphoblastoid cell lines in vitro and is an effective agent against L1210 leukemia in vivo. The present studies have examined the toxicity, and in some cases, metabolism, of CdA in (1) multiple established human cell lines of varying phenotype, (2) leukemia and lymphoma cells taken directly from patients, (3) normal bone marrow cells, and (4) normal peripheral blood lymphocytes. Nanomolar concentrations of CdA blocked the proliferation of lymphoblastoid cell lines with a high ratio of deoxycytidine kinase to deoxynucleotidase. The drug had virtually no effect on the growth of cell lines derived from solid tissues. The CdA inhibited the spontaneous uptake of tritiated thymidine by many T and non-T, non-B acute lymphoblastic leukemia cell specimens at concentrations less than or equal to 5 nM. The same concentrations did not impair either thymidine uptake or granulocyte-monocyte colony formation by normal bone marrow cells. In common with deoxyadenosine, but unlike several other agents affecting purine and purine metabolism, CdA was lethal to resting normal T lymphocytes and to slowly dividing malignant T cells. In both resting and proliferating lymphocytes, the CdA was phosphorylated by deoxycytidine kinase and entered a rapidly turning over nucleotide pool. Dividing lymphocytes also incorporated abundant CdA into DNA. The selective toxicity of CdA toward both dividing and resting lymphocytes may render the drug useful as an immunosuppressive or antileukemic agent.
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PMID:Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. 613 5

The in vitro and in vivo antineoplastic activity of 5-AZA-2'-deoxycytidine (5-AZA-CdR) and beta-2'-deoxythioguanosine (TGdR) on L1210 and L1210/ARA-C (resistant to cytosine arabinoside) leukemic cells was investigated. 5-AZA-CdR was a very potent cytotoxic agent against the L1210 leukemia cells. This analogue was inactive against L1210/ARA-C leukemic cells because these cells lack deoxycytidine kinase, the enzyme that converts 5-AZA-CdR to its active nucleotide form. TGdR was a potent cytotoxic agent to both L1210 and L1210/ARA-C leukemic cells. In mice which were injected simultaneously with both L1210 and L1210/ARA-C leukemic cells, the drug combination of 5-AZA-CdR plus TGdR had a very potent antineoplastic activity and produced long-term survivors. Either agent alone did not produce any long-term survivors in the mice with L1210 and L1210/ARA-C leukemia. This experimental model indicates that 5-AZA-CdR plus TGdR is an interesting drug combination for the treatment of leukemia with drug-resistant cells.
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PMID:Combinational chemotherapy of L1210 and L1210/ARA-C leukemia with 5-AZA-2'-deoxycytidine and beta-2'-deoxythioguanosine. 618 15

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

The 2-fluoro derivative of 9-beta-D-arabinofuranosyladenine (2-F-ara-A) and its soluble 5'-formate and 5'-phosphate derivatives were therapeutically effective against the parent leukemia L1210 (L1210/0). 2-F-ara-A and 9-beta-D-arabinofuranosyladenine 5'-formate were inactive aginst a 1-beta-D-arabinofuranosylcytosine-resistant subline (L1210/ara-C) that was deficient in deoxycytidine kinase. Deoxycytidine prevented 2-F-ara-A-induced inhibition of proliferation of L1210/0 cells in culture and alleviated 2-F-ara-a inhibition of DNA synthesis. After treatment of mice with 9-beta-D-arabinofuranosyladenine 5'-formate, intracellular levels of the 5'-triphosphate of 9-beta-D-arabinofuranosylfluoroadenine in leukemia cells were more than 10 times higher in L1210/0 cells than in L1210/ara-C cells. Similar results were obtained in this line of leukemia cells from mice treated with the 5'-monophosphate of 9-beta-D-arabinofuranosyl-2-fluoroadenine. Thus, L1210/ara-C cells deficient in deoxycytidine kinase activity were also deficient in capacity to phosphorylate 2-F-ara-A. Kinase activity from L1210/0 cells for deoxycytidine and for 2-F-ara-A coeluted from calcium phosphate cellulose and from diethylaminoethyl cellulose columns and had similar mobility on gel electrophoresis. Deoxyadenosine kinase was clearly separated from deoxycytidine kinase. Deoxycytidine competed with 2-F-ara-A for phosphorylation by the partially purified enzyme from L1210 cells. These results indicate that 2-F-ara-A is phosphorylated to the 5'-monophosphate by deoxycytidine kinase of leukemia L1210 cells.
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PMID:Metabolism and chemotherapeutic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. 625 36

The kinetics of cytosine arabinoside (AraC) were studied in vitro using P388 murine leukemia lines sensitive (P388-S) and resistant (P388-R) to the drug. Using P388-S cells, the 3H-thymidine index (L.I.) was paralleled by the 3H-AraC index, i.e. any cell in the S-phase of the cycle also incorporated the 3H-AraC into DNA. With the resistant line, the 3H-AraC index was zero in spite of high L.I. This discrepancy between the L.I. and 3H-AraC index could be used to predict the percentage of resistant cells when known mixtures of sensitive and resistant populations were used. The reason for lack of incorporation into DNA by the resistant cells was shown to be the presence of very low levels of the enzyme deoxycytidine kinase in P388-R cells resulting in an inability to phosphorylate AraC to its active form AraCTP. Immediate inhibition of DNA synthesis caused by AraC was directly proportional to the number of sensitive cells present in the population, but was not as accurate a predictor of sensitivity as the 3H-AraC index. Cloning in methylcellulose was found to be the least sensitive predictor of the percentage of sensitive and resistant cells, most likely related to the difference in cloning efficiency of the sensitive and resistant lines.
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PMID:Comparison of in vitro assays for detecting subpopulations of P388 leukemic cells resistant to AraC. 654 97


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