Comparative studies of leukemic cells sensitive and resistant to cytosine arabinoside

Chu, Ming; Fischer, Glenn A.

doi:10.1016/0006-2952(65)90198-x

Cited by 176 publications

(23 citation statements)

References 7 publications

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“…The mechanism of clinical resistance to these agents has not been defined; most resistant animal tumors appear to lack the kinase necessary for ara-C activation (37,38), but a recent study suggested a decreased response rate to ara-C in cases of AML having elevated deaminase activity before therapy, or showing a rise in deaminase levels during therapy with ara-C (11). In addition, Meyers et al have demonstrated the induction of cytidine deaminase in vitro in HeLa cells exposed to low levels of ara-C (39).…”

Section: Discussionmentioning

confidence: 99%

Purification and Properties of Cytidine Deaminase from Normal and Leukemic Granulocytes

Cn³

et al. 1974

J. Clin. Invest.

111

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A B S T R A C T Cytidine deaminiase, an enzyme that catalyses the deamination of both cytidine and its nucleoside analogues including the antineoplastic agents cytosine arabinoside (ara-C) and 5-azacytidine (5-azaC), lhas been partially purified from normal and leukemic humiian granulocytes. The purification procedure included lheat precipitation at 700 C, ammoniunm sulfate precipitation, calcium phosphate gel ionl exchange, and Sephadex G-150 gel filtration. The enzymlle has mol xvt 51,000, isoelectric pH of 4.8, and maximlum activity over a broad pH range of 5-9.5. The enzyme is stabilized by the presence of the sulfhydryl reagent, dithiothreitol.Cytidine deaminase from normal human graniulocytes lhas a greater affinity for its physiologic substrate cytidine (Km = 1.1 X 10-5 AM) than for ara-C (8.8 X 10-°MI) or 5-azaC (4.3 X 10' M). Halogenated analogues such as 5-fluorocytidine and 5-bromo-2'-deoxycytidine also exhiibited substrate activity, with maximum velocities greater than that of the physiologic substrates cytidine anid deoxycytidine. No activity was observed witlh nucleotides or (leoxyniucleotides. The relative maximumlii velocity of the enzyme for cytidine and its nucleoside analogues remaiie(l constanit during purification, inidicating that a single enzynme was responsible for deaminiatioln of these substrates.Tetrahydrouridine (THU) was founid to be a strong competitive inhibitor of partially purified deamiiinase with a KT of 5.4 X 10' M.The X 10'/nmg protein) than chronic myelocytic leukemia (CML) cells (1.40±0.70 X 10' U/mg proteini) or acute myelocytic leukemia (AML) cells (0.19+0.17 X 103 U/ mg protein). To explain these differences in enzyme levels in leukemic versus normal cells, the changes in cytidine deaminase levels associated with maturation of nornmal granulocvtes were studied in niormal human bone marrow. Myeloid precursors obtained from bone marrow aspirates were separated into mature and immature fractions by Ficoll density centrifugation. Deaminase activity in lysates of mature granulocytes was 3.55-14.2 times greater than the activity found in the lysates of immature cells. Decreased enzyme activity was also found in immature myeloid cells from a patient with CML as compared to mature granulocytes from the same patient. These observations support the conclusion that the greater specific activity of cytidine deaminase in normal mature granulocytes as compared to leukemic cells is related to the process of granulocyte maturation ratlher than a specific enzymatic defect in leukemic cells.

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Section: Discussionmentioning

confidence: 99%

Purification and Properties of Cytidine Deaminase from Normal and Leukemic Granulocytes

Cn³

et al. 1974

J. Clin. Invest.

111

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“…It may also be incorporated into cellular DNA (Chu & Fischer, 1965, 1968Silagi, 1965). At concentrations as low as 2o #g./ml., ara-C has been shown to inhibit replication of HSV (Rapp, 2964) Ti me (days) Fig.…”

Section: Resultsmentioning

confidence: 99%

Herpes Simplex Virus Latency in Cultured Human Cells Following Treatment with Cytosine Arabinoside

O’Neill

Goldberg

Rapp

1972

Journal of General Virology

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SUMMARYTreatment of human cell cultures infected with herpes simplex virus type e (HSV-2) with cytosine arabinoside resulted in the prevention of both virus cytopathology and synthesis of detectable infectious virus. Following removal of the inhibitor infectious HSV-2 reappeared and the cultures were destroyed. However, there was a delay of at least 5 to 6 days following inhibitor removal before infectious virus could be detected. The reappearance of infectious HSV-z was paralleled by virus cytopathology. The period between the disappearance and reappearance of infectious virus is defined as the latent period. Cultures during this period were as sensitive as control cultures to superinfection with HSV-z or vesicular stomatitis virus. Infectious centre assays performed with cultures during the latent period indicated that as many as I in 800 cells were capable of ultimately synthesizing infectious virus. Attempts to prevent the reappearance of infectious HSV-2 by treating infected cultures with cytosine arabinoside for up to 22 days were unsuccessful, thus indicating that HSV-2 can remain associated with the cells in a non-infectious form for an extended period without being degraded.

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“…Attention was focussed on 5'-deoxy derivatives which are unable to form 5'-phosphate esters, the proposed active forms of both agents (8)(9)(10). In the 5-fluorouracil series, 5 '-chloro-5-fluorouridine (6) and 5'-deoxy-5-fluorouridine (6) were later found to possess promising biological activities (1 1 -13).…”

Section: Introductionmentioning

confidence: 99%

Structure and conformation of 2′,5′-anhydroarabinosylcytosine: X-ray, ¹H nmr and ¹³C nmr analyses

Birnbaum¹,

Budêšínský²,

Beránek³

1987

Can. J. Chem.

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Crystals of 2',5'-anhydroarabinosylcytosine hemihydrate belong to the monoclinic space group P21. The cell dimensions are a = 9.643(2), b = 10.328(1), c = 10.544(2) A, P = 94.55!1)". X-ray intensity data were measured on a diffractometer and the structure was determined by direct methods. Least-squares refinement, which included all nucleoside hydrogen atoms, converged at R = 0.041 for 2298 observed reflections. The asymmetric unit contains two molecules of the nucleoside and one molecule of water. In both nucleoside molecules, the conformation about the glycosyl bond is anti, with XCN values of 15.5(3) and 26.3(3)", respectively. In the bicyclic sugar moiety, the arabinofuranose rings adopt a C(3')exo/C(2')endo conformation and are highly puckered (7, = 57"). The solution conformation was studied by 'H and I3C nmr spectroscopy. A difference nOe proton nmr spectrum and 3~(~,~) coupling constants reveal an anti conformation in solution, with torsion angles very similar to those obtained from X-ray analysis. A comparison of observed 3J(H,H) coupling constants with those calculated on the basis of a modified Kitrplus equation shows significant differences, probably due to the presence of the bicyclic system. Une comparaison des constantes de couplage 3~( H ,~) observkes avec celles calculCes en se basant sur une Cquation de Karplus modifiee prksente des differences notables qui sont probablement dues i la presence du systkme bicyclique.[Traduit par la revue]

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Comparative studies of leukemic cells sensitive and resistant to cytosine arabinoside

Cited by 176 publications

References 7 publications

Purification and Properties of Cytidine Deaminase from Normal and Leukemic Granulocytes

Purification and Properties of Cytidine Deaminase from Normal and Leukemic Granulocytes

Herpes Simplex Virus Latency in Cultured Human Cells Following Treatment with Cytosine Arabinoside

Structure and conformation of 2′,5′-anhydroarabinosylcytosine: X-ray, ¹H nmr and ¹³C nmr analyses

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Comparative studies of leukemic cells sensitive and resistant to cytosine arabinoside

Cited by 176 publications

References 7 publications

Purification and Properties of Cytidine Deaminase from Normal and Leukemic Granulocytes

Purification and Properties of Cytidine Deaminase from Normal and Leukemic Granulocytes

Herpes Simplex Virus Latency in Cultured Human Cells Following Treatment with Cytosine Arabinoside

Structure and conformation of 2′,5′-anhydroarabinosylcytosine: X-ray, 1H nmr and 13C nmr analyses

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Structure and conformation of 2′,5′-anhydroarabinosylcytosine: X-ray, ¹H nmr and ¹³C nmr analyses