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PubMed1986

Reaction kinetics and cytosine adducts of chloroethylene oxide and chloroacetaldehyde: direct observation of intermediates by FTNMR and GC-MS.

As it is not yet known which are the important miscoding adducts formed in the reaction of the relatively unstable compound chloroethylene oxide (CEO) with double-stranded DNA, proton FTNMR and GC-mass spectroscopy were used to directly detect and characterize reaction intermediates. Reaction of CEO with cytidine gave the (hydrated) 2-oxoethyl derivative at the N-3 position prior to ring closure to 3,N4-ethenocytidine; 5-methylcytosine gave an analogous reaction. However, reactions of CEO or chloroacetaldehyde (CAA) with 3-methylcytidine - i.e., with the N-3 blocked as in double-stranded DNA (ds DNA) - were shown by GC-MS of the silylated products to give, at a much slower rate, a pattern of at least 17 adducts all of which contained chlorine. Based on MS fragmentation and considerations of positional, optical and cis/trans isomerism, the reaction products of the 3-methylcytosine moiety were assigned as cis/trans N4-(2-chlorovinyl)-3-methylcytosine which may have arisen from the corresponding N4-(1-hydroxy-2-chloroethyl) adduct. It is postulated that formation of these cytosine-N4 adducts would be more rapid in double-stranded DNA than in the model compound, and that the N4-(2-chlorovinyl) group may be a miscoding adduct. The kinetics for CEO rearrangement, hydrolysis and nucleophilic attack have been studied by proton FTNMR and lead to the hypothesis that concerted nucleophilic attack by cytosine-N4 and CEO rearrangement produce the N4 adducts.

5-Methylcytosine↗
PubMed1979

Effect of coadministration of uracil or cytosine on the anti-tumor activity of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodents.

Concentration of 5-fluorouracil (5-FU) in the tumor, blood, and various organs of AH130-bearing rats after administration of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and uracil was examined. The concentration of 5-FU in blood was less than 0.02 microgram/ml with all combinations of FT-207 and uracil except high molar ratios of uracil to FT-207 (ratio, 5 and 10), whereas high concentrations of up to a maximum of 0.200 microgram/g on administration of uracil plus 5 or 7.5 mg/kg of FT-207 (ratio, 4), was found in the tumor. On oral administration of FT-207 plus uracil in various combinations, the highest T/B (ratio of concentration of 5-FU in the tumor to that in blood) value was obtained at a ratio of uracil to FT-207 of 4. With this combination, 5-FU concentration in the tumor, muscle, and spleen was higher than that after administration of FT-207 alone (5 mg/kg). These results suggest that at the clinical doses the optimum molar ratio of uracil to FT-207 is 4. Coadministration of cytosine enhanced the antitumor activity of FT-207 on sarcoma-180 in mice. However, cytosine enhanced the antitumor activity of FT-207 less than uracil and its coadministration resulted in a lower concentration of 5-FU in the tumor than coadministration of uracil.

Administration, Oral↗
PubMed1979

[Intragenome distribution of 5-methyl cytosine and reassociation kinetics of cow blood lymphocyte DNA under normal conditions and in chronic lymphoid leukemia].

The DNA from cow blood lymphocytes is methylated in a varying degree: the maximal content of 5-methyl cytosine (2,3 mol%) is found in the "instantly" renaturating sequences (Cot lett than 10(-4)), a relatively large amount (1,4 mol%)--in moderately repeated sequences (Cot = 10(-4)--400) and the minimal amount (0,9 mol%) in the unique sequences (Cot greater than 400). In their reassociation kinetics, GC-content and other physico-chemical properties the blood lymphocyte DNA of the controls and of animals with chronic lymphoid leukemia appear to be similar. Consequently, the genome organization of leukemic animals does not change significantly; a considerable decrease of 5-methyl cytosine of lymphocyte DNA in lymphoid leukemia parallels the decrease of genome methylation in the leukemic cells. This decrease does not affect the unique sequences, but involves all types of repeated sequences (moderately and frequently repeated ones and palindromes). It is assumed that the specific disturbances in genome methylation under lymphoid leukemia may be a cause of transcription deficiences and cell transformations.

Animals↗
PubMed1984

Radiation-induced crosslinking of cytosine.

Formation of dimers upon gamma irradiation of cytosine, 2'-deoxycytidine, and 2'-deoxycytidine-5'-monophosphate in N2O-saturated aqueous solutions was found to be a major process. Quantitative measurements revealed that more than 50% of OH adduct radicals of cytosine undergo dimerization. Derivatized dimers and monomeric products were separated and tentatively identified by combined capillary gas chromatography-mass spectrometry.

Cobalt Radioisotopes↗
PubMed1983

Mutation by [5-3H]cytosine decay in DNA of Escherichia coli lacking uracil-DNA glycosylase activity.

The mutagenic local effect of tritium decay at the 5 position of cytosine in DNA of Escherichia coli was determined in wild-type and in ung strains defective in uracil-DNA glycosylase. In the absence of this in vivo activity any genetic consequences of uracil residues formed in DNA should be enhanced. However, the mutation frequency response was no greater in the mutant strain than in the wild type. This finding is inconsistent with the earlier suggestion that efficient production of C to T transitions by the local effect of [5-3H]cytosine decay results from the formation of uracil in cellular DNA. Some other intermediate should be considered, one that is not a substrate for uracil-DNA glycosylase.

Cytosine↗
PubMed1981

[Genetic effects of the breakdown of tritium incorporated into Saccharomyces cerevisiae yeast cells. IV. The lethal and mutagenic effects and the nature of the mutations induced by tritium breakdown in the 5th position of cytosine].

We have studied in lethal and mutagenic effects and the nature of mutations induced by 3H decays in the 5-th position of cytosine (5-3H-C). The lethal efficiency was determined as alpha 1 = (10.3 +/- 6.7) x 10(-3) decay-1 or alpha 1 = (12.9 +/- 9.4) x 10(-5) rad-1 and the mutagen efficiency for ade1, ade2 genes -- as alpha m = (4.3 +/- 2.3) x 10(-7) decay-1 or alpha m = (5.4 +/- 2.9) x 10(-9) rad-1. For ade2 gene the spectrum of mutations induced by 5-3H-C was as follows: 1% of frameshifts and 99% of base pair substitutions -- 9% of transversions, 3% of AT leads to GC transitions and 87% of GC leads to AT transitions. Our results establish the 5-3H-C as one of the most effective and specific mutagens reported so far for yeast. According to the scheme of Krasin with coworkers, the final product of 3H decay in the 5-th position of cytosine is uracil. Our calculations show that more than 90% of uracil residues are removed from the yeast genome by cell repair systems.

Cytosine↗
PubMed1994

Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor.

Successful expression of the cytosine deaminase (CD) suicide gene in vivo is demonstrated in three weakly immunogenic murine tumor models: the 102 and 205 fibrosarcomas and the 38 adenocarcinoma. Normal mammalian cells do not contain cytosine deaminase, but tumor cells transduced with retroviral vectors containing the CD gene metabolize the relatively nontoxic prodrug 5-fluorocytosine to the highly toxic 5-fluorouracil. In vitro cells expressing the CD gene are killed by 5-fluorocytosine while unmodified cells are not. When injected into syngeneic mice, CD+ tumors can also be eliminated in vivo by systemic treatment with 5-fluorocytosine without significant toxicity to the host. Animals whose CD+ tumors were eliminated with prodrug treatment resist subsequent rechallenge with unmodified wild type tumor. This posttreatment immunity appears to be tumor specific. Applications of the CD system in gene therapy models are discussed.

Animals↗
PubMed1993

A first step in the development of gene therapy for colorectal carcinoma: cloning, sequencing, and expression of Escherichia coli cytosine deaminase.

We have developed a new approach involving gene therapy for the treatment of primary and metastatic tumors in the liver. As a first step toward the development of this gene therapy treatment for metastatic colorectal carcinoma, the Escherichia coli gene that encodes cytosine deaminase (CD) (EC 3.5.4.1) has been cloned. By using positive genetic selection, a plasmid carrying a 10.8-kilobase BamHI/EcoRI DNA insert was isolated that had CD enzymatic activity. Genetic screening, followed by enzymatic assays, identified a 3-kilobase DNA fragment that retained CD activity. Deamination of cytosine and 5-fluorocytosine (5-FC) by cloned CD was demonstrated. DNA and protein sequencing identified an open reading frame of 427 amino acids that encodes CD. To demonstrate that expression of CD in eukaryotic cells allows metabolism of the nontoxic prodrug 5-FC to the toxic metabolite 5-fluorouracil, CD was cloned into a eukaryotic expression vector and transfected into a human colorectal carcinoma cell line. Growth inhibition studies showed a shift in the IC50 for 5-FC from 17,000 microM in the parental cell line to 30 microM in cells expressing CD.

Amino Acid Sequence↗
PubMedDate not supplied

Enzyme/prodrug gene therapy approach for breast cancer using a recombinant adenovirus expressing Escherichia coli cytosine deaminase.

A recombinant adenovirus expressing Escherichia coli cytosine deaminase (AdCD) was constructed with the purpose of exploring its utility for the treatment of breast cancer. Infection of the human breast cancer cell line, MDA-MB-231, with AdCD resulted in high levels of cytosine deaminase enzyme activity. MDA-MB-231 cells infected with AdCD were 1000-fold more sensitive to 5-fluorocytosine (5-FC) than cells infected with a control adenovirus. Cell mixing experiments indicated that only 10% of AdCD-infected cells in a population were needed to induce complete cytotoxicity of noninfectious cells exposed to 5-FC. This suggests that bystander effects play an important role in AdCD-mediated cytotoxicities. Direct injection of AdCD into human breast MDA-MB-231-derived tumors grown as xenografts in nude mice, followed by daily intraperitoneal injection 5-FC was sufficient to inhibit tumor growth. These results suggest that in vivo gene therapy for breast cancer using AdCD is feasible.

Adenoviridae↗
PubMed1977

Kinetics of deamination of cytosine nucleosides with etherified sugar hydroxyls.

The kinetics of deamination of derivatives of the therapeutically important 1-beta-D-arabinofuranosylcytosine with etherified (methylated) sugar hydroxyls has provided additional direct evidence for involvement of the 2'-hydroxyl in intramolecular catalysed deamination. In the case of 1-beta-D-lyxofuranosylcytosine, the kinetics of deamination of its 2'-O-methyl and 3'-O-methyl derivatives pointed to similar involvement of the "up" 2'-OH in intramolecular catalysed deamination. Participation by the 3'-OH, which is also in the "up" position, was excluded. A qualitative correlation was shown to exist between the electron density distributions on C(4) and C(6) of the cytosine rings in cytosine, 1-methylcytosine and cytidine, and their relative susceptibilities to deamination.

Cytidine↗
PubMed1997

Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts.

Gene therapy combined with radiation therapy to enhance selectively radiation cytotoxicity in malignant cells represents a new approach for cancer treatment. We investigated the efficacy of adenoviral (Ad5)-directed cytosine deaminase/5-fluorocytosine (CD/5-FC) enzyme/prodrug gene therapy to enhance selectively the tumoricidal action of ionizing radiation in human cancer xenografts derived from a human squamous carcinoma cell line (SQ-20B). Tumor xenografts grown in hindlimbs of nude mice were transfected with an adenoviral vector (Ad.CMV.CD) containing the cytosine deaminase (CD) gene under the control of a cytomegalovirus (CMV) promoter. Mice were injected i.p. with 800 mg/kg of 5-FC for 12 days, and tumors were treated with fractionated radiation at a dose of 5 Gy/day to a total dose of 50 Gy. In larger tumors with a mean volume of 1069 mm3, marked tumor regression to 11% of the original tumor volume was observed at day 21 (P = 0.01). The volumetric regression of smaller tumors with a mean volume of 199 mm3, which received the same combined treatment protocol, was significant at day 12 (P = 0.014). However, unlike large tumors, regression of the smaller tumors continued until day 36 (P = 0.01), with 43% cured at day 26. No cures or significant volumetric reduction in size was observed in tumors treated with radiation alone; Ad.CMV.CD with or without radiation; or with Ad.CMV.CD and 5-FC. These results suggest that the CD/5-FC gene therapy approach is an effective radiosensitizing strategy and may lead to substantial improvement in local tumor control that would translate into improved cure rates and better survival.

Adenoviruses, Human↗
PubMedDate not supplied

A pair of single-strand and double-strand DNA cytosine-N4 methyltransferases from Bacillus centrosporus.

Sequence analysis of the BcnI restriction-modification system revealed the presence of an open reading frame encoding a second cytosine-N4 methyltransferase, M.BcnIA, in the vicinity of the genes specifying the previously characterized cytosine-N4 methyltransferase M.BcnIB and restriction endonuclease R.BcnI. Both methyltransferases were purified from the E. coli cells expressing the individual genes, and their enzymatic efficiencies in vitro were compared with a variety of DNA substrates. Both enzymes act on 5'-CC(C/G)GG-3' sites in double-stranded DNA, however, M.BcnIA can also, with a comparable efficiency, modify the specific targets in single-stranded DNA. The biological significance of the presence of the tandem methyltransferases in the BcnI system is discussed.

Bacillus↗
PubMed1975

Comparative study of cytosine arabinoside therapy alone and combined with thioguanine, mercaptopurine, or daunorubicin in acute myelocytic leukemia.

Three hundred twenty-six patients with acute myelocytic leukemia were randomly and prospectively assigned to four therapeutic regimens: cytosine arabinoside either alone or in combination with daunorubicin, 6-mercaptopurine, or 6-thioguanine. The results in 231 qualified previously untreated patients were analyzed. The combination treatments produced a significantly greater frequency of complete or partial remission than single drug therapy. Treatment with cytosine arabinoside and thioguanine led to 48% age-adjusted complete and partial responses. The median sur survival from diagnosis of all 66 evaluable patients treated with these two drugs was 18 weeks, while the median survival for those who responded to this combination was 15 months.

Adult↗
PubMed1979

Paraplegia following intrathecal cytosine arabinoside.

Paraplegia following prophylactic intrathecal cytosine arabinoside (Ara-C) is described in a patient with acute myelogenous leukemia in remission who received doses of 100 mg/m2/d for 5 consecutive days. Cerebrospinal fluid examination prior to the last dosage of cytosine arabinoside revealed a mononuclear pleocytosis and increased protein. The neurological manifestations developed within one week after the last dose of Ara-C and persisted for over 8 weeks. Administration of intrathecal Ara-C in the same dose over longer intervals within 3-5 days between consecutive doses resulted in mild, transient neurological symptoms (paresthesias) in only one of 30 patients so treated.

Adult↗
PubMed1981

Phase II trials of Baker's antifol, bleomycin, CCNU, streptozotocin, tilorone, and 5-fluorodeoxyuridine plus arabinosyl cytosine in metastatic breast cancer.

A total of 202 patients with advanced breast cancer were entered into two prospectively randomized Phase II trials conducted by the Eastern Cooperative Oncology Group, in an effort to identify promising agents and combinations for previously treated cases. Patients in Study 1 received bleomycin, CCNU, or streptozotocin and those in Study 2 received tilorone, Baker's antifol, or a combination of 5-fluorodeoxyuridine plus arabinosyl cytosine. Partial responses were seen only with bleomycin, Baker's antifol, and 5-fluorodeoxyuridine plus arabinosyl cytosine. The median times to treatment failure ranged from 3.6 weeks to 5.7 weeks, and the median survival times, from 8 weeks to 25 weeks for tilorone and bleomycin, respectively. Toxic reactions was primarily hematologic and gastrointestinal, but skin, neurologic, respiratory, and renal abnormalities were noted in some treatment arms. The treatment schedules outlined and the toxic effects noted provide background information that might prove useful in designing complex new chemotherapeutic programs, since there is pharmacological rationale for incorporating some of the agents tested into present standard combination chemotherapy regimens.

Antineoplastic Agents↗
PubMed1983

Ocular toxicity from high-dose cytosine arabinoside.

A patient with refractory acute myelogenous leukemia was treated with high-dose cytosine arabinoside (3.0 g/m2 every 12 hours). Following ten doses over five days the patient developed excessive tearing, photophobia, burning ocular pain, and blurred vision. Ophthalmologic examination revealed conjunctival injection, central punctate corneal opacities with subepithelial granular deposits, and decreased visual acuity. Symptoms gradually resolved over the following four days; however, impaired visual acuity persisted for two weeks and corneal opacification did not disappear until four weeks following therapy. Prior and subsequent administration of cytosine arabinoside according to the same dose schedule for only four doses over two days and eight doses over four days were well tolerated and did not produce ocular toxicity. It is suggested that ocular toxicity results from inhibition of corneal epithelial DNA synthesis and is related to both drug dosage and duration of drug exposure. Strategies should be explored to eliminate this treatment-limiting adverse effect of potentially effective therapy.

Cornea↗
PubMed1984

Malignant histiocytosis. Response to VP-16-213 and cytosine arabinoside.

A patient with malignant histiocytosis who relapsed after receiving an Adriamycin (doxorubicin)-containing combination and radiation therapy subsequently had a complete remission on VP-16-213 and cytosine arabinoside. She remains free of disease 32 months after achieving a complete remission. VP-16-213 and cytosine arabinoside (Ara-C) deserve further evaluation in the treatment of this neoplasm.

Aged↗