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PubMed2002

Cyclopentenyl cytosine increases the phosphorylation and incorporation into DNA of 1-beta-D-arabinofuranosyl cytosine in a human T-lymphoblastic cell line.

The cytotoxic effect of 1-beta-D-arabinofuranosyl cytosine (araC) depends on the intracellular phosphorylation into its active compound araCTP, on the degree of degradation of araCTP and on the incorporation of araCTP into DNA. Deoxycytidine triphosphate (dCTP) inhibits the phosphorylation of araC (by feedback inhibition of the enzyme deoxycytidine kinase) and the incorporation of araCTP into DNA (by competition for DNA polymerase). In a T-lymphoblastic cell line, we studied whether the cytotoxicity of araC (2 nM-50 microM) could be enhanced by decreasing the concentration of dCTP, using the nucleoside-analogue cyclopentenyl cytosine (CPEC), an inhibitor of the enzyme CTP synthetase. Preincubation of the cells with CPEC (100-1,600 nM) for 2 hr increased the concentrations of araCMP 1.6-9.5-fold, which was significant for each concentration of CPEC used. The concentration of araCDP remained low, whereas the concentration of araCTP changed depending on the concentration of araC used. With 2-15 microm of araC and a preincubation with 400 nM of CPEC, the araCTP concentration increased by 4-15% (not significant), and the total amount of araC nucleotides increased significantly by 21-45%. When using a concentration of araC of 2 nM after a preincubation with CPEC of 100 nM, the concentration of araCMP increased by 60% (p = 0.015), whereas that of araCTP decreased by 10% (p = 0.008). This was compensated by an increase of 41% (p = 0.005) of araCTP incorporation into DNA, which represented 43% of all araC metabolites. Moreover, by performing pulse/chase experiments with 400 nM of CPEC and 2 microM of araC, the retention of cytosolic araCTP and the incorporated amount of araCTP into DNA were increased by CPEC. The modulation by CPEC of araC metabolism was accompanied by a synergistic increase of araC-induced apoptosis and by an additive effect on the araC-induced growth inhibition.

Antineoplastic Agents↗
PubMed1978

Antitumor activity of prolonged-release derivative of cytosine arabinoside, cytosine arabinoside-agarose conjugate.

A prolonged-release derivative of cytosine arabinoside (Ara-C), cytosine arabinoside-agarose bead conjugate (Ara-C-AB), was synthesized and its pharmaceutical and pharmacological characteristics were examined. Ara-C was released successively for considerably long period from Ara-C-AB in vitro. Following intraperitoneal injection of 3H-Ara-C-AB, radioactivity could be detected in plasma and urine of BDF1 mouse for four days, while 3H-Ara-C administered as a free form was excreted completely in the first 24 hr. Increase in lifespan of L1210 leukemia-bearing mice was demonstrated after intraperitoneal injection of Ara-C-AB with both the dosage schedules of three days before and one day after inoculation of L1210 cells at the dose of 30 mg equivalent Ara-C/kg.

Animals↗
PubMed1987

Size of the directing moiety at carbon 5 of cytosine and the activity of human DNA(cytosine-5) methyltransferase.

M13 DNAs in which carbon 5 of each deoxycytidine residue in one strand is replaced with a bulky group are very good substrates for human DNA (cytosine-5) methyltransferase. Rate enhancements of up to 35 fold are obtained depending on the size of the moiety at C-5. The enzyme appears optimally suited to sense a methyl group in one strand at this position. Alkaline density gradient analyses of the distribution of methyl groups applied to 5-BrdCyd or 5-IdCyd substituted DNA reveal that these groups serve to direct the enzyme to methylate the unsubstituted strand.

Cytosine↗
PubMed2005

Determination of 5-methyl-cytosine and cytosine in tumor DNA of cancer patients.

The determination of the relative methylation in DNA tumor samples, in order to evaluate the activity of some anti-cancer drugs, has become a very important issue in the clinical field. Capillary electrophoresis (CE) applications in this area have been done previously but no good separation for model samples or tumor samples has been reported. In this work, the CE conditions have been optimized in order to obtain baseline separation and efficient peaks for cytosine and 5-methylcytosine in both, standard mixtures and actual tumor samples; other bases (adenine, uracil, guanine, and thymine) have also been integrated in the optimization studies. More efficient peaks and shorter analysis time compared with the already reported conditions have been obtained employing a fused-silica capillary (75 microm inner diameter) of 44.5 cm effective length, 20 mM carbonate buffer (pH 9.6) plus 80 mM sodium dodecyl sulfate, a separation voltage of 20 kV, and detection at 223 nm.

5-Methylcytosine↗
PubMed2001

DNA interstrand crosslink formation by mechlorethamine at a cytosine-cytosine mismatch pair: kinetics and sequence dependence.

Expansion of the triplet repeat DNA sequence d[CGG]n.d[CCG]n is a characteristic of Fragile X syndrome, a human neurodegenerative disease. Stable intrastrand conformations formed by both d[CGG]n and d[CCG]n, and involving G-G and C-C mismatch pairs, respectively, are believed to be of importance in the development of the disease. We have shown previously that C-C mismatch pairs can be crosslinked covalently by mechlorethamine, a nitrogen mustard alkylating agent, and hence this reaction may be of value as a probe for conformers of d[CCG]n. To characterize the mechlorethamine C-C crosslink reaction further, here we report the kinetics and sequence dependence of formation of the crosslink species, using a series of model duplexes. The rate of reaction depends on the base sequence proximal to the C-C mismatch pair. Hence, in 19mer duplexes containing a central d[M4M3M2M1Cn1n2n3n4].d[N4N3N2N1Cm1m2m3m4] sequence, where M-m and N-n are complementary base pairs, the amount of crosslink increased with increasing G-C content of the eight base pairs neighboring the C-C mismatch and with the proximity of the G-C pairs to the C-C mismatch. Molecular dynamics simulations of the solvated duplexes provided an explanation of these data. Hence, for a C-C pair flanked by G-C base pairs the mismatched cytosine bases remain stacked within the duplex, but for a C-C pair flanked by A-T base pairs, the simulations suggested local opening of the duplex around the C-C pair, making it a less effective target for mechlorethamine.

Alkylating Agents↗
PubMed2000

Gilbert's conjecture: the search for DNA (cytosine-5) demethylases and the emergence of new functions for eukaryotic DNA (cytosine-5) methyltransferases.

In 1985 Walter Gilbert challenged members of the DNA methylation community assembled at a National Institutes of Health meeting organized by Giulio Cantoni and Ahron Razin with the following words: "The most exciting aspect about the methyl groups on DNA is the thought that they might provide a locally inherited change in a DNA structure. However, for that to be interesting, those changes have to be different in different cells. Furthermore, the alterations in methylation have to be freely imposable and have to be maintained. It is not yet clear that all these properties are true. So I don't think one will find that methylation ever is one of the primary, top-level controls on gene expression."In essence, Gilbert's conjecture, that DNA methylation is not one of the top-level controls on gene expression, assumes that evidence in favor of both of its testable propositions will not be obtained. Evidence for the first proposition, that alterations in methylation status associated with gene-expression states have to be maintained, was already available in 1985 and has been strengthened by a number of very recent experiments. However, the extensive effort to obtain evidence for the second proposition, that alterations in methylation status be freely imposable, has not been successful in its original intent. The effort has, on the other hand, resulted in the emergence of new functions for 5-methylcytosine and the cytosine methyltransferases in eukaryotic DNA repair, recombination and chromosome stability.

Alleles↗
PubMed1989

On the possible role of cytosine deamination in delayed photoreversal mutagenesis targeted at thymine-cytosine dimers in E. coli.

While delayed photoreversal (PR) mutagenesis has been interpreted as a measure of misincorporation step in targeted mutagenesis, the specificity to produce glutamine tRNA suppressor mutations (C to T transitions) at sites in DNA where a thymine-cytosine dimer (T = C) may target mutation suggests a deamination model: deamination T = C to T = U and trans-U DNA replication after PR. We describe here two enquires that did not support the latter model: (a) Uracil DNA glycosylase activity as estimated from the restricted plating efficiency of phage T5 containing uracil-substituted DNA showed no variation that might allow an exceptional opportunity for mutation at U in DNA, and (b). The kinetics of delayed PR mutagenesis were unaltered if UV-irradiated cells were held in buffer suspension for 2 h at 41 degrees C (a procedure known to allow deamination T = C to T = U) and then assayed. Other results with cells containing both umuC and ung (uracil DNA glycosylase) defects showed the magnitude of T = C deamination sufficient to provide T = U at the critical site of mutation to an extent greater than the mutation frequencies produced by delayed PR mutagenesis, and considerations of the kinetics led to the suggestion that the deamination model could apply if there were an optimum period 30-130 min post-UV for efficient recovery of DNA replication after PR. The results underscored the feasibility of delayed PR mutagenesis by deamination and trans-U replication, but a selection between the two models could not be determined.

Base Sequence↗
PubMedDate not supplied

Application of monoclonal antibodies against cytosine deaminase for the in vivo clearance of a cytosine deaminase immunoconjugate.

The selective delivery of anticancer drugs to tumors vs normal tissue using targeted antibody-enzyme conjugates for prodrug activation is limited by the amount of drug generated by blood-borne enzyme. Clearance of non-tumor-associated conjugate would increase the tumor/blood conjugate ratio, and enable larger amounts of prodrugs to be administered. A method for clearing the monoclonal antibody (mAb) conjugate L6-cytosine deaminase (L6-CD) was established by using an antibody raised against CD. The mAb 102-26 was obtained by immunizing BALB/C mice with CD conjugated to keyhole limpet hemocyanin. 102-26 was able to precipitate purified CD from solution as assessed by radioimmune precipitation and recognized CD in Western blot analyses. Similar studies were used to establish that 102-26 also recognized CD when conjugated to the L6 and 1F5 mAbs. Selective removal of L6-CD from the circulation of nude mice bearing H2981 human lung adenocarcinoma (L6-antigen positive) was achieved by injecting 102-26 24 h after L6-CD administration. High T/B ratios were obtained by clearance of a L6-CD (38:1 compared to 1.3:1 without clearance).

Adenocarcinoma↗
PubMed1994

Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase.

The gene encoding cytosine deaminase (CD) has been expressed in the human colorectal carcinoma cell line WiDr. Metabolism studies confirm that tumor cells expressing CD convert the very nontoxic prodrug 5-fluorocytosine (5FCyt) to 5-fluorouracil (5FUra) and 5FUra metabolites. Tumor xenografts composed of CD-expressing cells can selectively generate tumor levels of > 400 microM 5FUra when the host mouse is dosed with nontoxic levels of 5FCyt. The selective metabolic conversion of 5FCyt to 5FUra in CD-expressing tumor cells results in the inhibition of thymidylate synthase and incorporation of 5FUra into RNA. 5FUra is also liberated into the surrounding environment when CD-expressing tumor cells are treated with 5FCyt. The liberated 5FUra is able to kill neighboring, non-CD-expressing tumor cells in vitro and in vivo. Most importantly, when only 2% of the tumor mass contains CD-expressing cells (98% non-CD-expressing cells), significant regressions in all tumors are observed when the host mouse is dosed with nontoxic levels of 5FCyt.

Animals↗
PubMed1994

1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl] cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine with improved therapeutic index in vivo.

1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne (cyclic [cHPMPC]) was evaluated as a novel antiviral agent in comparison with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Evaluation for in vitro activity against herpes simplex virus type 2 in MA-104 and MRC-5 cells showed that both cHPMPC and HPMPC have comparable activities and cytotoxicities. cHPMPC was found to be stable on incubation in human plasma and human liver homogenates. Intracellular metabolism studies revealed that cHPMPC was converted inside of the cells to HPMPC and then to the monophosphate, the diphosphate, and the monophosphate choline metabolites. In a mouse herpes simplex virus type 2 encephalitis model, both cHPMPC and HPMPC exhibited similar potencies in vivo. Nephrotoxicity, which is the dose-limiting toxicity of HPMPC, was assessed in a 14-day repeated-dose toxicity study in rats; cHPMPC has an improved safety margin of > or = 13-fold over that of HPMPC.

Animals↗
PubMed2003

High-resolution magnetic resonance imaging of the efficacy of the cytosine analogue 1-[2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl]-N(4)-palmitoyl cytosine (CS-682) in a liver-metastasis athymic nude mouse model.

High-resolution magnetic resonance (MR) imaging techniques in a liver metastatic mouse model were used to assess CS-682, a novel 2'-deoxycytidine analogue of 1-[2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl]-N(4)-palmitoyl cytosine. The efficacy of CS-682 was visualized in real time by MR imaging of initial seeding and subsequent growth of liver metastases. The relative therapeutic efficacies of CS-682 and two agents used clinically, gemcitabine [2'-deoxy-2',2'-difluorocytidine monohydrochloride (DFDC)] and 5-fluorouracil (5-FU), were compared in this model. CS-682 was found to exhibit superior efficacy by delaying the onset and inhibiting the growth of liver metastasis compared with gemcitabine, 5-FU, and control. The overall occurrence of metastases was decreased 62% by CS-682, 18% by DFDC, and 35% by 5-FU. CS-682 increased the life span of the treated animals significantly, by 28 days above the 29-day median survival without treatment, compared with 11 days by DFDC and 14 days by 5-FU. The increased survival in CS-682-treated animals correlated with the antimetastatic activity of this compound. These preclinical findings support the potential clinical utility of CS-682 in the treatment of liver metastasis.

Animals↗
PubMed1978

[Sister chromatid exchanges under bromine incorporation into DNA cytosine nucleotides. II. Utilization of 3H-deoxycytidine as a DNA cytosine precursor].

The incorporation of 3H-deoxycytidine (3H-Cdr) in the presence of thymidine (Tdr) into cultured human blood lymphocytes has been studied. The analysis of the label in interphase nuclei as well as in chromosomes at metaphase was carried out. The labeling was much higher when 3H-Cdr (0.5 to 1.0 C/ml, 2--4 x 10(-5) mM) was added to the cultures simultaneously with Tdr (4 x 10(-1) mM). This observation is considered as an indication that in the presence of high doses of Tdr exogeneous Cdr is utilized to synthesize cytosine of DNA rather than thymidine. During the first hours after its addition, the bulk of 3H-Cdr is eliminated from the culture medium. At 12 hrs of the incubation, the medium seems to be free of the nucleoside as shown particularly from the single chromatid localization of the label in chromosomes of the second mitosis. The incorporation into lymphocytes of 3H-Tdr administered in the same dose under the same conditions was registered for the whole period of observation (24 hrs). The data obtained are discussed in relation to lymphocyte catabolism of exogeneous nucleosides.

Bromodeoxycytidine↗
PubMed1987

Abrogation of the prognostic significance of low leukemic cell retention of cytosine arabinoside triphosphate by intensification of therapy and by alteration in the dose and schedule of administration of cytosine arabinoside.

The ability of leukemic cells to phosphorylate cytosine arabinoside (araC) and retain the triphosphate form of the drug (araCTP) is strongly predictive of remission duration for patients with acute nonlymphocytic leukemia who are treated with araC-based maintenance therapy. An increase in the intensity of therapy improves the overall median duration of remission, the increased intensity of therapy being especially beneficial for patients whose leukemic cells do not retain araCTP. This alteration in therapy reduces the prognostic significance of leukemic cell araCTP retention. Further, it seems that the use of high-dose araC as intensive consolidation therapy and the administration of conventional-dose araC by continuous infusion make it possible to further reduce or even abrogate the adverse prognostic significance of low leukemic cell retention of araCTP.

Acute Disease↗
PubMed1999

A prospective randomized trial of KRN8602 and cytosine arabinoside vs. daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. The KRN8602 Leukemia Study Group.

A prospective randomized study was conducted to compare the efficacy and toxicity of two anthracyclines for the treatment of patients with acute myelogenous leukemia (AML). Fifty-eight patients were randomized and received induction therapy consisting of cytosine arabinoside (AraC) 100 mg/m2/day for 7 days combined with either KRN8602 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride [KRN]) 15 mg/m2/day for 5 days (KRN/AraC group) or daunorubicin (DNR) 40 mg/m2/day for 3 days (DNR/AraC group). Complete remission rate was 78.6% (22/28) in the KRN/AraC group and 73.1% (19/26) in the DNR/AraC group. There was a higher incidence of nausea/vomiting and anorexia observed in the KRN/AraC group compared to the DNR/AraC group, while the incidence of other adverse effects (stomatitis, diarrhea, and infectious complications) were similar between both groups. No electrocardiogram (ECG) abnormalities were observed after treatment in the KRN/AraC group, while in the DNR/AraC group, one patient showed ECG abnormality and three patients exhibited either arrhythmia, heart failure, or tachycardia. Mental disorder was reported in two cases in the KRN/AraC group. These findings suggest that KRN/AraC is similar in effectiveness to DNA/AraC but more toxic in central nervous system and gastrointestinal symptoms and less toxic regarding cardiac function in patients with previously untreated AML.

Adolescent↗
PubMed1992

Intracellular cytosine arabinoside accumulation and cytosine arabinoside triphosphate formation in leukemic blast cells is inhibited by etoposide and teniposide.

Cytosine arabinoside (ara-C) is one of the most active compounds in the treatment of acute leukemias. In the majority of current protocols ara-C is combined with other cytotoxic agents in an attempt to increase antileukemic activity. The present study investigated the impact of etoposide, teniposide, amsacrine, mitoxantrone, anthracyclines, and asparaginase on the cellular accumulation of ara-C and its intracellular metabolism in order to provide a better rationale for combination therapy. Intracellular accumulation and phosphorylation of ara-C were determined in peripheral blast cells from twenty patients with acute leukemias after exposure to 1 and 10 mumol/l ara-C alone and after preincubation with 1 and 10 micrograms/ml etoposide, 10 and 100 micrograms/ml teniposide, 10 mumol/l amsacrine, 500 ng/ml mitoxantrone (or daunorubicin or doxorubicin) or 10 mumol/l asparaginase. Ara-C accumulation at 10 mumol/l was decreased by 1 microgram/ml etoposide (67 +/- 18% of control), 10 micrograms/ml etoposide (30 +/- 22%), 10 micrograms/ml teniposide (12 +/- 23%), 100 micrograms/ml teniposide (10 +/- 18%), and amsacrine (51 +/- 21%). Intracellular ara-CTP formation was determined at an extracellular concentration of 10 mumol/l and preincubation with these drugs. The intracellular formation of ara-CTP was decreased by 1 microgram/ml etoposide (77 +/- 15% of control), 10 micrograms/ml etoposide (32 +/- 22%), 10 micrograms/ml teniposide (10 +/- 9%), 100 micrograms/ml teniposide (0 +/- 0%), but not by amsacrine. These data indicate that prior exposure to etoposide and teniposide influence ara-C metabolism and possibly cytotoxicity, and thus should not immediately precede ara-C administration in clinical trials.

Acute Disease↗
PubMed1991

Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia.

4'-Demethoxydaunorubicin (idarubicin [IDR]) is a new anthracycline that differs from its parent compound by the deletion of a methoxy group at position 4 of the chromophore ring. This minor structural modification results in a more lipophilic compound with a unique metabolite that has a prolonged plasma half-life as well as in vitro and in vivo antileukemia activity. To determine its activity in acute myelogenous leukemia (AML), 130 consecutive adult patients between the ages of 16 and 60 with newly diagnosed disease were randomized in a single institution study to receive either IDR in combination with cytosine arabinoside (Ara-C) or standard therapy with daunorubicin (DNR) and Ara-C. The trial was analyzed using the O'Brien-Fleming multiple testing design that allowed for periodic inspection of the data at specific patient accession points. After accrual of 60 patients per arm, analysis showed that patients who received IDR/Ara-C had a superior response compared with those who received standard therapy: 48 of 60 patients (80%) achieved complete remission on the former arm compared with 35 of 60 patients on the latter (58%, P = .005). Logistic regression analysis of factors associated with complete response indicated that treatment with IDR/Ara-C offered a significant advantage to patients who presented with a high initial white blood cell count compared with treatment with DNR/Ara-C. The degree of marrow aplasia was approximately the same on each arm as was nonhematologic toxicity. Overall survival for patients on the IDR/Ara-C arm was 19.5 months compared with 13.5 months on the DNR/Ara-C arm (P = .025) at a median follow-up of 2.5 years. We conclude that IDR/Ara-C can effectively replace standard therapy with DNR/Ara-C in adult patients less than age 60 with newly diagnosed AML.

Adult↗
PubMed1991

Aclarubicin plus cytosine arabinoside versus daunorubicin plus cytosine arabinoside in previously untreated patients with acute myeloid leukemia: a Danish national phase III trial. The Danish Society of Hematology Study Group on AML, Denmark.

A regimen of aclarubicin (ACR) of 75 mg/m2 daily for 3 days plus a continuous intravenous infusion of cytosine arabinoside (ara-C) of 100 mg/m2 per day for 7 days was compared with daunorubicin (DNR) 45 mg/m2/day for 3 days plus ara-C for 7 days as first-line chemotherapy of de novo acute myeloid leukemia (AML) in a randomized, nationwide Danish study. A total of 180 patients aged between 17 and 65 years were entered onto the protocol. Patients who achieved complete remission (CR) were given five courses of intensive consolidation therapy consisting of two courses of high dose ara-C, two courses of amsacrine plus etoposide, and one course of DNR plus ara-C. Of 174 evaluable patients, 99 achieved CR. The rate of CR was significantly higher on ACR plus ara-C than on DNR plus ara-C [66% versus 50% (p = 0.043)] and decreased significantly with increasing age. The hematological toxicity was identical for the two regimens. A total of 83 patients entered consolidation therapy. At 4 years, 37% of patients with CR following ACR were still in remission compared with 33% following DNR (p = 0.48), and the total survival at 4 years was 29% versus 20% (p = 0.26). The duration of remission and total survival both decreased with increasing age. ACR plus ara-C seem at least as good or better than DNR plus ara-C as first-line chemotherapy of AML.

Aclarubicin↗