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At least 19 recordsLinked to original sources
PubMed1986

Interaction of deoxycytidine and deoxycytidine analogs in normal and leukemic human myeloid progenitor cells.

The inhibitory effects of three deoxycytidine analogs, 1-B-D-arabinofuranosylcytosine (Ara-C), 5-aza-2'-deoxycytidine (DAZ) and Ara-5-azacytosine (AAC) were compared with respect to the clonogenic behavior of human promyelocytic leukemic cells (HL-60), a deoxycytidine kinase deficient subvariant (HL-60/Ara-C), and normal human myeloid progenitor cells (CFU-GM). When cells were continuously exposed to each agent for 7 days, Ara-C was the most inhibitory, DAZ slightly less effective and AAC the least inhibitory on a molar basis. HL-60/Ara-C were also highly cross-resistant to both DAZ and AAC. In the absence of deoxycytidine, all three agents were either equally inhibitory or slightly more inhibitory to the growth of CFU-GM than to HL-60, whereas administration of deoxycytidine in ten to one-hundred fold excess protected CFU-GM to a greater extent than HL-60. In contrast, administration of high concentrations of drugs, e.g. 10(-5)-10(-4) M, in conjunction with excess deoxycytidine exhibited greater toxicity toward CFU-GM than toward HL-60/Ara-C. Coadministration of deoxycytidine in ten-fold excess reduced the total intracellular accumulation and DNA incorporation of each analog in HL-60 cells by approx. 50%, whereas a hundred fold excess was associated with greater than a 90% reduction in these values. These studies demonstrate that deoxycytidine may antagonize the effects of Ara-C, DAZ and AAC in both normal and leukemic human myeloid cells, and that at low drug concentrations the degree of protection may be greater for normal elements. However, regimens employing high drug concentrations in conjunction with deoxycytidine do not appear to exert a selective inhibitory effect toward a highly resistant leukemic subvariant. These data suggest that alternative deoxycytidine/deoxycytidine analog dose relationships and schedules must be sought which are capable of selectively eradicating resistant cells.

Azacitidine↗
PubMed1987

High degree of resistance to 5-aza-2'-deoxycytidine in L1210 cells in vitro associated with almost complete loss of deoxycytidine kinase activity.

In L1210 mouse leukemic cells the resistance towards 5-aza-2'-deoxycytidine was developed in vitro by stepwise selection in increasing concentrations of this drug. According to the respective IC50 values the variant cell line was at least 7000-fold more resistant to 5-aza-2'-deoxycytidine, 3300-fold to arabinosyl 5-azacytosine and 20,000-fold to arabinosyl cytosine in comparison to the parental cell line. The uptake of radioactivity derived from 5-aza-2'-deoxycytidine in variant cells was depressed by 95% as compared to the parental strain and no uptake occurred in case of 2'-deoxycytidine. The phosphorylation of this natural precursor and of its analog in the presence of the cell-free system derived from the variant cell line was nearly completely abolished. In resistant cells the amount of DNA 5-methyl-cytosine relative to cytosine was decreased by 24-44%.

5-Methylcytosine↗
PubMed1987

Effect of deoxycytidine on the metabolism and cytotoxicity of 5-aza-2'-deoxycytidine and arabinosyl 5-azacytosine in normal and leukemic human myeloid progenitor cells.

The effect of deoxycytidine (dCyd) on the inhibitory effects of two antileukemic nucleoside analogs, 5-aza-2'-deoxycytidine and ara-5-aza-Cyd, toward the clonogenic growth of normal human bone marrow progenitors (CFU-GM) and leukemic blast progenitors (L-CFU) was examined. Continuous exposure of cells to 10(-6)-10(-5) M 5-aza-deoxycytidine or 10(-5)-5 x 10(-5) M ara-5-aza-Cyd in conjunction with a 10- 100-fold excess of dCyd resulted in significantly greater restoration of CFU-GM growth than L-CFU colony formation at each dose relationship. Normal bone marrow mononuclear cells exposed to 10(-3) M dCyd for 4 hr (along with 5-aza-dCyd or ara-5-aza-Cyd) exhibited intracellular deoxycytidine triphosphate (dCTP) pools 20-fold higher than their leukemic counterparts. However, this finding was not associated with enhanced analog incorporation into leukemic cell DNA. These results suggest that high concentrations of dCyd preferentially protect normal versus leukemic progenitor cells from the inhibitory actions of 5-aza-dCyd and ara-5-aza-Cyd. They also raise the possibility that this in vitro selectivity may be related to enhanced expansion of dCTP pools in normal bone marrow elements and involves factors other than differential short-term analog incorporation into DNA.

Acute Disease↗
PubMed1986

Analysis of 5-fluoro-2'-deoxycytidine and 5-trifluoromethyl-2'-deoxycytidine and their related antimetabolites by high-performance liquid chromatography.

An isocratic, ion-paired, reversed-phase high-performance liquid chromatography technique for the quantitative determination of 5-fluoro-2'-deoxycytidine (FdCyd) and 5-trifluoromethyl-2'-deoxycytidine (F3methyldCyd) and their related antimetabolites is described. Extraction and purification of these compounds from DNA, RNA, and free pools is reviewed diagrammatically. Total analysis time including quantitation of DNA and RNA primary constituents is 45 min. Average combined recoveries for prodrugs and antimetabolites is above 90% with standard deviations of 0.07 and 0.58 and average precisions of 5.51 and 8.30% for FdCyd and F3methyldCyd, respectively. Average coefficients of variation were 3.8 +/- 0.5% for FdCyd and 7.7 +/- 1.0% for F3methyldCyd. Limits of detection were approximately 1 pmol for unlabelled prodrugs and antimetabolites. FdCyd, when generally tritiated with a specific activity of 18 Ci/mmol, was detected in the 5 X 10(-15)-20 X 10(-15) mol (fmol) range depending on sample condition.

Buffers↗
PubMed1987

Deamination rates of 1-beta-D-arabinofuranosylcytosine, deoxycytidine and 5-methyl-2'-deoxycytidine in seven hematopoietic cell lines.

Enzymatic deamination activity was determined with tritium-labelled substrates in seven established hematopoietic cell lines, in order to compare deamination rates in intact vs. broken cells with cytosine arabinoside, deoxycytidine and 5-methyldeoxycytidine. Deaminase activity was found in all the cell lines, although it was very low in mouse leukemia L1210 cells. The deamination activity of intact cells varied from 1.0 to 38.3 pmoles/micrograms protein/30 min, being highest in the human null-cell ALL line (NALL-1), the human promyelocytic leukaemia line (HL-60) and the human T-ALL line (JM). The variation in specific activities in the broken cells was between 0.9 and 30.2 pmoles/micrograms protein/30 min. The deamination rate of deoxycytidine was in general higher than that of 5-methyldeoxycytidine or cytosine arabinoside.

Animals↗
PubMed1987

Deoxycytidine kinase and deoxycytidine deaminase values correspond closely to clinical response to cytosine arabinoside remission induction therapy in patients with acute myelogenous leukemia.

In this study, it has been shown that in 21 patients with AML the dCyd kinase and dCyd deaminase activities correspond closely to the clinical response to ara-C remission induction therapy. Patients with primary disease were treated with a conventional-dose ara-C regimen whereas nonresponders and relapsed patients followed an ID ara-C regimen (1 g/m2 X 12). Of these 21 patients (11 with primary disease and ten relapsed), seven had ara-C resistant disease (three primary and four relapsed patients). Five of the seven patients had a very low dCyd kinase and normal dCyd deaminase activity, whereas the other two had a normal dCyd kinase and an increased dCyd deaminase activity.

Adolescent↗
PubMed1985

Deoxycytidine therapy in two patients with adenosine deaminase deficiency and severe immunodeficiency disease.

Two children with adenosine deaminase (ADA) deficiency and combined immunodeficiency disease were given parenteral deoxycytidine in order to reverse the severe T-cell immunodeficiency associated with this disease. One patient received a total of three courses of parenteral deoxycytidine. On two occasions deoxycytidine (50 mg/kg/day) was infused intravenously continuously for 2 weeks. During one of the infusions she received the deoxycytidine deaminase inhibitor tetrahydrouridine (THU). Steady-state levels of plasma deoxycytidine increased 4-fold with THU. RBC dCTP/dATP increased more than 10-fold after 48 hr of deoxycytidine infusion. Immunologic studies following the intravenous infusion of deoxycytidine showed transient improvement in T-cell immunity. The third course of deoxycytidine (50 mg/kg/day) was administered subcutaneously during a 10-hr night-time infusion. After 6 and 12 weeks of nightly subcutaneous infusions, there was minimal improvement in the in vitro immunologic studies and no clinical improvement. The second patient received a single 2-week course of continuous intravenous deoxycytidine (50 mg/kg/day) following which there was no significant change in T-cell immunity. This study defines some of the pharmacologic parameters of human deoxycytidine metabolism and suggests that some patients with ADA deficiency may respond to deoxycytidine therapy with improvement in T-cell-mediated immunity, although the changes are small and the effect on clinical status appears to be limited.

Adenosine Deaminase↗
PubMed1989

Kinetic properties and inhibition of human T lymphoblast deoxycytidine kinase.

The kinetic properties of 50,000-fold purified cultured human T lymphoblast (MOLT-4) deoxycytidine kinase were examined. The reaction velocity had an absolute requirement for magnesium. Maximal activity was observed at pH 6.5-7.0 with Mg:ATP for 1:1. High concentrations of free Mg2+ or free ATP were inhibitory. Double reciprocal plots of initial velocity studies yielded intersecting lines for both deoxycytidine and MgATP2-. dCMP was a competitive inhibitor with respect to deoxycytidine and ATP. ADP was a competitive inhibitor with respect to ATP and a mixed inhibitor with respect to deoxycytidine. dCTP, an important end product, is a very potent inhibitor and was a competitive inhibitor with respect to deoxycytidine and a non-competitive inhibitor with respect to ATP. TTP reversed dCTP inhibition. The data suggest that (a) MgATP2- is the true substrate of deoxycytidine kinase; (b) the kinetic mechanism of deoxycytidine kinase is consistent with rapid equilibrium random Bi Bi; (c) deoxycytidine kinase may be regulated by its product ADP and its end product dCTP as well as the availability of deoxycytidine. While many different nucleotides potently inhibit deoxycytidine kinase, their low intracellular concentrations make their regulatory role less important.

Adenosine Triphosphate↗
PubMed1989

Cytosine arabinoside kills postmitotic neurons: evidence that deoxycytidine may have a role in neuronal survival that is independent of DNA synthesis.

Cytosine arabinoside (ARA C), a competitive inhibitor of the incorporation of 2'-deoxycytidine into DNA in other cell types, caused a concentration-dependent inhibition of KCl- and insulin-stimulated survival of postmitotic ciliary parasympathetic ganglion neurons, and the nerve growth factor (NGF)-stimulated survival of postmitotic dorsal root ganglion (DRG) sensory neurons in vitro. The IC50 for survival was 2 x 10(-8) M for both types of neurons after 4 d under the culture conditions used. The inhibition of DRG survival by ARA C in the presence of varying concentrations of NGF indicated that ARA C acted as an apparent noncompetitive antagonist of NGF. This cytotoxic effect of ARA C was blocked by 2'-deoxycytidine, but not by cytosine, 2'-deoxyadenosine, 2'-deoxyguanosine, or 2'-deoxythymine, indicating that ARA C was interfering with a deoxycytidine-specific survival process. Cytidine could block ARA C toxicity, but it was 40 times less potent than 2'-deoxycytidine. The blockade of the cytotoxic effect of ARA C by 2'-deoxycytidine indicated that 2'-deoxycytidine was an apparent competitive antagonist of ARA C toxicity. 2'-Deoxycytidine, by itself, was not survival-promoting. Other antimitotic agents, such as adenine arabinoside, thymine arabinoside, 5-fluorodeoxyuridine, 5-bromodeoxycytidine, 5-azadeoxycytidine, and aphidicolin had no effect on neuronal survival at a concentration 5000 times the EC50 of ARA C, indicating that inhibition of DNA synthesis or repair was probably not the mechanism by which ARA C inhibited neuronal survival and that other 2'-deoxynucleosides were not involved in the survival-promoting process. Nitrobenzylthioinosine, an inhibitor of 2'-deoxycytidine and ARA C membrane transport in other cell types, inhibited the cytotoxic effect of ARA C in neurons, suggesting that ARA C entered the neurons through a similar transport mechanism and that ARA C needed to gain access to the inside of the neuron to be effective. These results indicate that ARA C, in addition to being an antimitotic agent for dividing cells, is also cytotoxic for postmitotic neurons. This inhibition of neuronal survival by ARA C is hypothesized to be due to inhibition of a 2'-deoxycytidine-dependent process that is independent of DNA synthesis or repair. Thus, 2'-deoxycytidine may have an important and previously unrecognized role in cellular function that in the case of neurons is critical for survival.

Animals↗
PubMed1979

Depression of DNA synthesis in mouse spleen after treatment with 5-aza-2'-deoxycytidine.

5-Aza-2'-deoxycytidine is a highly effective cytostatic agent that preferentially affects the lymphatic system. Pretreatment of noninbred H mice with the drug markedly depressed the level of thymidine (dThd) incorporation into DNA in the spleen and also lowered the dThd and thymidylate kinase activities. Maximum effects were observed following administration of the analog in a single dose 24 hours before the mice were killed. Whereas cytidine and dThd did not reverse the inhibitory effect of 5-aza-2'-deoxycytidine, excessive doses of deoxycytidine partially reversed this inhibition. Similar to the depression of dThd incorporation, a depression in the incorporation of deoxycytidine and cytidine into spleen DNA was found after 24-hour pretreatment with 5-aza-2'-deoxycytidine. However, 7 days following 5-aza-2'-deoxycytidine treatment, the incorporation of dThd into DNA in the spleens of mice was significantly increased. [3H]5-aza-2'-deoxycytidine was rapidly incorporated into spleen DNA, whereas deoxycytidine interfered with the incorporation of [3H]5-aza-2'-deoxycytidine.

Animals↗
PubMed1986

Deoxycytidine reverses inhibition of morphogenesis by thymidine in young chick blastoderm.

Exogenous thymidine affects morphogenesis of the early chick blastoderm possibly by depleting the deoxycytidine triphosphate pool. The aim of this study is to determine whether the inhibitory action of thymidine on early chick blastoderm morphogenesis is alleviated by the removal of thymidine and/or treatment with deoxycytidine. Chick blastoderms at the full hypoblast stage develop abnormally in egg albumen containing 1.23 X 10(-3) M thymidine. Development is normal when deoxycytidine is included simultaneously in the culture medium with thymidine at equimolar concentrations. Blastoderms were cultured in egg albumen containing 15 microCi/ml thymidine [methyl-3H] or 10 microCi/ml deoxycytidine [5-3H], and 1.2 X 10(-3) M 2'-deoxycytidine or 1.23 X 10(-3) M thymidine, respectively. The culture was interrupted at timed intervals, and the amount of radioactivity associated with DNA was determined. Exogenous deoxycytidine in the culture medium caused a noticeable increase in the incorporation of 3H-thymidine, while exogenous thymidine markedly inhibited the uptake and incorporation of 3H-deoxycytidine into DNA of blastoderms. Thymidine does not inhibit the expansion of blastoderm, the migration of cells for formation of the primitive streak (PS), and the induction of axial tissues, but it interferes with the organization of these tissues to form the embryonic axis. Blastoderms show slight signs of recovery when thymidine is removed. Deoxycytidine counteracts the action of thymidine and seems to be a rate-limiting factor in normal differentiation of the early chick blastoderm.

Animals↗
PubMed1992

Increased deoxycytidine kinase activity in cancer cells and inhibition by difluorodeoxycytidine.

The activity of deoxycytidine kinase (EC 2.7.1.74), an important pyrimidine salvage enzyme, was elevated 5- to 30-fold in human ovarian carcinoma and OVCAR-5 cells, in human colon carcinoma and HT-29 cells, in rat hepatoma 3924A solid tumors and cells, and in rat sarcoma as compared with the respective control normal cells. There was an inverse relationship between cell doubling time and deoxycytidine kinase activity in 8 cancer cell lines, with rapidly growing HL-60 cells (20 hr) showing the highest, and slower-growing lung H69 cells (60 hr) the smallest, increase in enzyme activity. In time-sequence studies in human HL-60, OVCAR-5, PANC-1, and rat hepatoma 3924A cells, there was a significant rise in deoxycytidine kinase activity after 3-6 hr of seeding, with peak increases (3.5- to 4-fold) at 48-72 hr in the log phase in comparison with values of the respective plateau phase cells (96-144 hr). In extracts of various cancer cells, the high deoxycytidine kinase activity was competitively inhibited by difluorodeoxycytidine (DFDC), with Ki = 7 to 30 microM. The Km for deoxycytidine in various carcinoma cell lines ranged from 0.3 to 0.7 mM and addition of DFDC increased the apparent Km from 0.7 to 4 mM. Deoxycytidine kinase activity in human HL-60 cells was inhibited by the end product, dCTP, with IC50 = 3 microM; dCTP elevated the Km for deoxycytidine from 0.35 to 0.9 mM. dTTP reversed the inhibition by dCTP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗