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 distribution of arabinosylcytosine (ara-C) and its metabolites has been measured in the liver, small intestine, spleen, and kidney of mice inoculated ip 5-6 days earlier with L1210 leukemia cells. Two major metabolites were found in the tissues--the nucleotides and the deaminated inactive product, arabinosyluracil (ara-U). The decay curve of ara-C in most of these tissues was curvilinear; the ara-C half-lives estimated from the terminal phases were 8. 11, 12, and 12 hr for spleen, kidney, intestine, and liver tissues, respectively. The ara-C half-life was not correlated with the deoxycytidine deaminase activity in the tissues. However, the deaminase activity in vitro correlated well with the amount of ara-U present in vivo. Similar analyses were made for L1210 leukemic cells and ascites fluid. A high nucleotide level was found in the cells and a significant amount of nucleotides was also identifiable in the ascites fluid. The activities of deoxycytidine kinase, but not of deoxycytidine deaminase, in host tissues of mice inoculated with L1210 leukemic cells sensitive to ara-C were greater than in those of normal mice. The phosphorylating activities in vitro correlated with the amount of nucleotide present in vivo in mice bearing L1210 leukemic cells. However, the infiltration of leukemic cells containing high kinase activities into the host tissues accounted for most, if not all, of the nucleotide level in these tissues. This is further evidenced by the fact that inoculating mice with L1210 leukemic cells resistant to ara-C did not alter the kinase activity or nucleotide levels of the host tissues; these resistant cells contain negligible amounts of ara-C phosphorylating activities.
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PMID:Correlation of mouse tissue distribution of arabinosylcytosine in vivo with enzymatic activities in vitro. 0 36

1-beta-D-Arabinofuranosylcytosine (cytarabine; ara-C) and 5-azacytidine (5-azaCR), cytosine nucleoside antimetabolites with different mechanisms of action, are both effective in the treatment of human leukemia, and the clinical use of these two agents in combination has been suggested. We have studied the therapeutic effect in L1210 leukemic mice of single i.p. doses of ara-C and 5-azaCR in combination. Therapeutic effects observed depended markedly on the sequence and time interval between the doses of each agent. Antagonism was observed when both agents were administered simultaneously. The optimal therapeutic effect was observed when 5-azaCR was administered after ara-C at a time when tumor DNA synthesis had maximally recovered after the ara-C dose. The dose-interval effect and correlation with recovery of DNA synthesis capacity were also observed in studies in vitro in which the survival of L1210 cells in culture was examined. ara-C was shown to inhibit the incorporation of [4-14C]-5-azaCR-derived radioactivity into DNA of L1210 cells in culture, and the therapeutic effects observed are interpreted in terms of these latter results and the mechanisms of action of the two agents.
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PMID:Combination chemotherapy of L1210 leukemia with 1-beta-D-arabinofuranosylcytosine and 5-azacytidine. 5 29

The degree to which anticancer drugs suppressed incorporation of tritiated thymidine into leukaemic cells was measured in 26 patients with acute leukaemia. Subsequent achievement of remission correlated best with suppression by cytosine arabinoside (ara-C). 6 of 7 patients with acute myelocytic and myelomonocytic leukaemia whose cells demonstrated suppression by ara-C of 3H-thymidine incorporation of 15% or less of control counts subsequently achieved remission, while 4 of 6 patients whose cells showed smaller degrees of inhibition did not achieve remission. Patients with acute lymphocytic leukaemia showed a similar pattern.
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PMID:Prediction of therapeutic response in acute leukaemia. 7 70

5-Azacytosine arabinoside (ara-AC) can be considered a combination of structural elements derived from the antitumor nucleosides cytosine arabinoside (ara-C) and 5-azacytidine (5-AC). The synthesis of ara-AC, for which standard methods were inadequate, was accomplished using the stable dihydro derivative as a synthetic intermediate. A novel dehydrogenation of the latter through the application of a trimethylsilylation-oxidation procedure gave ara-AC in good yield. Using murine L1210 leukemia as a test system, ara-AC was evaluated for antitumor properties in parallel determinations with 5-AC and ara-C. Although higher dose levels were necessary, ara-AC demonstrated a reproducibly greater efficacy in the L1210 system (% ILS = 144-148) than that shown by 5-AC (% ILS = 126-124) or ara-C (% ILS=127-121 ). Moreover, initial data suggest that ara-AC exhibits less host toxicity than either 5-AC or ARA-C. Although ara-AC can equally be considered an analogue of either 5-AC or ara-C, preliminary results indicate that ara-AC is chemically similar to 5-AC but biologically more closely related to ara-C.
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PMID:Synthesis and antitumor activity of 5-azacytosine arabinoside. 9 67

Replicating transforming functions of Rauscher leukemia virus (RLV) and the RLV pseudotype of Moloney sarcoma virus in mouse embryo fibroblasts were found to be most sensitive to inhibition by cytosine arabinoside (ara-C) 30 to 90 min after infection. The initiation of intracellular RLV DNA synthesis was detected by nucleic acid hybridization within this time interval. Treatment of infected cells with cytosine arabinoside abolished RLV DNA synthesis. Peak synthesis of the DNA complementary to the infecting RLV genome, the (-) strand, occurred 40 to 60 min after infection. During this interval two s two species of DNA were observed with estimated molecular weights of 0.5 X 10(5) to 1.0 X 10(5) and 3 X 10(6). Peak synthesis of the (+) strand viral DNA occurred 50 to 70 min after infection. The initial species detected had a molecular weight of 1.5 X 10(5) to 4.0 X 10(5) which shifted as a function of time to 3 X 10(6). Both (+) strand species were initially detected in the cytoplasm followed by a rapid (10-min interval) appearance of the faster-sedimenting species in the nucleus. The virus-specific (-) and (+) strand DNA species are presumably unintegrated intermediates in provirus formation.
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PMID:Kinetics of murine type C virus-specific DNA synthesis newly infected cells. 17 Apr 17

We have synthesized an analog (ara-CDP-DL-dipalmitin) of cytidine diphosphate diglyceride (CDP-diglyceride) in which the antitumor drug, cytosine arabinoside, is substituted for the cytidine moiety. Enzymes in rat and human liver convert this analog to phosphatidylinositol, thereby releasing cytosine arabinoside-5'-monophosphate, an obligatory intermediate in the activation of cytosine arabinoside. Unlike cytidine diphosphate diglyceride, however, ara-CDP-DL-diapalmitin is not an efficient substrate for phosphatidylglycerophosphate synthesis in liver or phosphatidylserine in Escherichia coli. The antitumor activity of ara-CDP-DL-dipalmitin in mice bearing L5178Y leukemia is described.
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PMID:A phospholipid derivative of cytosine arabinoside and its conversion to phosphatidylinositol by animal tissue. 19 10

The enzyme that phosphorylates 1-beta-D-arabinofuranosylcytosine (ara-C) was examined in rat ascites hepatomas to clarify whether the capacity for the phosphorylation of ara-C would be related to natural resistance of the tumors to ara-C. Ara-C kinase activity in AH-66F cells, which were moderately sensitive to ara-C, was approximately the same as that in the bone marrow of tumor-bearing rats. L-1210 leukemia, which is sensitive to ara-C, had a higher activity of the enzyme than the mouse bone marrow. On the other hand, the naturally resistant hepatomas, AH-60C, AH-109A, and AH-66, were low in their ara-C kinase activity. The enzyme activity in the cytoplasmic extract (30,000 g supernatant) of the tumor and bone marrow cells was nearly proportional to the capacity for ara-C phosphorylation in intact cells. Thus, the mechanism of natural resistance to ara-C in rat ascites hepatomas was attributed mainly to the low levels of ara-C kinase activity itself. Apparent Km of the enzyme for ara-C was about 170 micron. However, probably due to the presence of the uncompetitive type of inhibitor(s), the level of apparent Km lowered close to 40 micron at higher concentration of the protein as the source of the enzyme, showing similarity to the value in intact cells.
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PMID:Phosphorylation of 1-beta-D-arabinofuranosylcytosine by the cell-free extract of rat ascites hepatoma, in relation to the mechanism of natural resistance. 21 38

1-beta-D-Arabinofuranosylcytosine diphosphate choline was formed from 1-beta-D-arabinofuranosylcytosine (ara-C) during incubation in vitro of peripheral myeloblasts from patients with acute myelogenous leukemia and cultured cells (nonleukemic human lymphocytes, mouse lymphoma L5178Y, and HeLa); as well, 1-beta-D-arabinofuranosylcytosine diphosphate choline was formed in vivo in mouse leukemia L1210 cells and mouse liver. 3-Deazauridine enhanced the anabolism of ara-C in nonleukemic lymphocytes in vitro and leukemia L1210 cells in vivo but did not influence ara-C anabolism in the other cell types. In acute myelogenous leukemia myeloblasts incubated in vitro with ara-C, concentrations of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate were maximal after 8 hr of incubation and formation of the latter preceded that of 1-beta-D-arabinofuranosylcytosine diphosphate choline.
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PMID:Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline in neoplastic and normal cells. 27 75

a-beta-D-arabinofuranosylcytosine (ara-C) trapped in multilamellar liposomes exerted enhanced chemotherapeutic effect against L1210 murine leukemia. Among four types of liposomes, the one composed of sphingomyelin, stearylamine and cholesterol was most potent in enhancing chemotherapeutic effect of ara-C. And the findings that ara-C was released gradually from liposome in vitro and that ara-C in liposome was chemotherapeutically effective against subsequently inoculated L1210 cells suggested that slow but long-lasting release of ara-C from liposome was partially responsible for enhanced chemotherapeutic effect.
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PMID:Enhancement of chemotherapeutic effect by entrapping 1-beta-D-arabinofuranosylcytosine in lipid vesicles and its mode of action. 27 98

A limited number of biologically active materials were examined for their relative ability to selectively inhibit the replication of Gross or Rauscher murine leukemia virus (MLV) in Swiss mouse embryo cells by means of the UV-XC plaque-reduction assay. Among the compounds demonstrating significant antiviral activity against Gross MLV in vitro were 1-(4-fluorobenzyloxy) adenosine (FBAR), polyadenylic acid [poly(A)], the carbocyclic analogue of 6-methylthiopurine ribonucleoside (C-MeMPR), 3-(2,4-dinitrophenylhydrazonemethyl)rifamycin SV (AF/DNFI), and phosphonoacetic acid (PAA). Five compounds that exhibited significant antiviral activity against MLV in vitro were tested for similar activity against Rauscher MLV in vivo. Three of these selected compounds, pyrazofurin (pyrazomycin), ribavirin (Virazole), and 9-beta-D-arabinofuranosyladenine (ara-A), produced a significant (50%-100%) inhibition of virus-induced splenomegaly development in mice, whereas the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, failed to demonstrate any in vivo activity in this 21-day leukemogenesis assay. The administration of an inhibitor of adenosine deaminase (Co-vidarabine) in combination with ara-A resulted in an enhanced antiviral response in both infected cell cultures and animals. Co-vidarabine also increased the potency of ara-AMP against Gross MLV in vitro, indicating the probable dephosphorylation of the compound to ara-A and its subsequent deamination to ara-H in this system.
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PMID:Selective inhibition of RNA tumor virus replication in vitro and evaluation of candidate antiviral agents in vivo. 28 Jan 46


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