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PubMed2022

Suppression of trinucleotide repeat expansion in spermatogenic cells in Huntington's disease.

Trinucleotide repeats (TNRs) are dispersed throughout the human genome. About 20 loci are related to human diseases, such as Huntington's disease (HD). A larger TNR instability is predominantly observed in the paternal germ cells in some TNR disorders. Suppressing the expansion during spermatogenesis can provide a unique opportunity to end the vicious cycle of genetic anticipation. Here, using an in vitro differentiation method to derive advanced spermatogenic cells, we investigated the efficacy of two therapeutic agents, araC (cytarabine) and aspirin, on stabilizing TNRs in spermatogenic cells. Two WT patient-derived induced pluripotent stem cell (iPSC) lines and two HD hiPSC lines, with 44 Q and 180 Q, were differentiated into spermatogonial stem cell-like cells (SSCLCs). Both HD cell lines showed CAG tract expansion in SSCLC. When treated with araC and aspirin, HD1 showed moderate but not statistically significant stabilization of TNR. In HD2, 10 nM of aspirin and araC showed significant stabilization of TNR. All cell lines showed increased DNA damage response (DDR) gene expression in SSCLCs while more genes were significantly induced in HD SSCLC. In HD1, araC and aspirin treatment showed general suppression of DNA damage response genes. In HD2, only FAN1, OGG1, and PCNA showed significant suppression. When the methylation profile of HD cells was analyzed, FAN1 and OGG1 showed significant hypermethylation after the aspirin and araC treatment in SSCLC compared to the control. This study underscores the utility of our in vitro spermatogenesis model to study and develop therapies for TNR disorders such as HD.

Male↗
PubMed1977

The effect of cytosine arabinoside on the frequency of single-strand breaks in DNA of mammalian cells following irradiation or chemical treatment.

1-beta-D-Arabinofuranosyl cytosine (araC), a pyrimidine nucleoside analog used in the treatment of malignant tumors [1, 2], inhibits ultraviolet repair of DNA in a reversible manner. The inhibition occurs during the resynthesis-ligation step and is apparent at all sites undergoing repair. By use of araC it was possible to substantiate the reported observation that the initial velocities of ultraviolet repair are dose dependent and that hamster and human cells are more efficient that mouse cells in excising DNA damage after fluences of less than 50 J/m2. araC does not strongly inhibit gamma-ray-induced repair, although alkali-labile sites are removed more slowly in araC-treated cells. Repair of damage to DNA by N-methyl-N-nitrosoguanidine, mitomycin C, 4-nitroquinoline oxide and 8-hydroxyquinoline is strongly inhibited by araC.

4-Nitroquinoline-1-oxide↗
PubMed1977

Multiple basis of combination chemotherapy.

In combination chemotherapy, the type of drug interactions can be divided into three broad categories: 1) combinations based on cooperative effects of active drugs; 2) combinations in which the effectiveness of an active drug is increased by the concurrent administration of an inactive agent; and 3) combination of an active drug with an agent capable of selectively reversing the toxicity of the first drug. Many concepts have been proposed to explain the synergistic interaction between two active drugs at the level of the target cell. These include multiple inhibition of a single enzyme, enhanced activation, decreased inactivation, increased drug uptake, sequential blockade, concurrent inhibition, complimentary inhibition, and concerted inhibition. The therapeutic advantage of combination chemotherapy may reside in the whole organism, reflecting increased bioavailability of drug, reduced dose-limiting toxicity or reduced impairment of host defenses; it may reside in the tumor cells, reflecting the multiple molecular mechanisms of interaction mentioned above. Examples discussed include among others methotrexate plus citrovorum factor, thymidine or allopurinol, araC plus tetrahydrouridine and 3-deazauridine plus testosterone.

Animals↗
PubMed1976

Reactions of 2-acyloxyisobutyryl halides with nucleosides. Synthesis and biological evaluation of some 3"-acyl and 3',5'-diacyl derivatives of 1-beta-D-arabinofuranosylcytosine.

Previous papers in this series have described efficient syntheses of 3'-O-acyl and 3',5'-di-O-acyl and 3',5'-di-O-acyl derivatives of 2,2'-anhydro-1-(beta-D-arabinofuranosyl)cytosine hydrochloride (1,3). It has now been shown that the 2,2'-anhydro linkage in 1 and 3 can be selectively and efficiently cleaved by treatment with a mixture of pyridine and methanol giving the corresponding 3'-O-acyl derivatives of 1-beta-D-arabinofuranosylcytosine (2,4). The selective hydrolysis of the more soluble derivatives can also be achieved using either aqueous pyridine or a mixture of sodium carbonate and sodium bicarbonate in aqueous dioxane. Using the above procedures 3'-O-acyl araCs and 3',5'-di-O-acyl araCs with saturated or unsaturated ester groups containg from 2 to 22 carbon atoms have been prepared, and these substances have been evaluated for cytotoxicity and antiviral activity in tissue culture and for antitumor activity these substances have been evaluated for cytotoxicity and antiviral activity in tissue culture and for antitumor activity against L1210 leukemia in mice. Many of the compounds show high anti-L1210 activity relative to araC itself.

Anhydrides↗
PubMed1979

Interaction between mutant alleles of araC of the Escherichia coli B/r L-arabinose operon.

Strains were constructed that contain mutational alterations affecting two distinct functional domains within the araC gene protein. The araCi (catabolite repression insensitivity) and araCh (catabolite repression hypersensitivity) mutations were used to alter the catabolite repression sensitivity domain, and mutation to D-fucose resistance was used to alter the inducer binding domain. araCh, D-fucose-resistant double mutants never exhibited constitutive ara operon expression, whereas all of the araCi, D-fucose-resistant double mutants did exhibit constitutivity. When L-arabinose was used as an inducer, most of the double mutants exhibited the sensitivity to catabolite repression associated with the araCi or araCh mutation. However, when D-fucose was used as an inducer, changes in sensitivity to catabolite repression were observed that were attributed to interactions between the two protein domains. The roles of catabolite activator protein and araC gene protein in the induction of the araBAD operon were discussed.

Alleles↗
PubMed1979

A radioimmunoassay for cytosine arabinoside.

A radioimmunoassay (RIA) for cytosine arabinoside (AraC) has been developed using antiserum raised in a sheep to an AraC monophosphate-ovalbumin conjugate. The antibody shows only 0.008% cross-reactivity with uracil arabinoside (AraU) and low (0.023%) cross-reactivity with other commonly co-administered drugs such as cytotoxic and antibacterial agents, and also a number of naturally occurring nucleosides and nucleotides. It does however cross-react by 125% with AraC monophosphate and by 109% with AraC triphosphate. As little as 1 ng/ml of AraC can be detected in plasma, serum, urine and cerebrospinal fluid (CSF) with no need for prior extraction. This RIA has been used to follow the disappearance of AraC from the plasma of patients receiving the drug.

Animals↗
PubMed1978

Regulatory properties of araC(c) mutants in the L-arabinose operon of escherichia coliB/r.

Merodiploids containing a high-constitutive and a low-constitutive araC(c) allele were assayed for constitutive expression of the ara operon. Low-constitutive araC(c) alleles either were unable to repress the constitutive rate of ara operon expression exhibited by by high-constitutive araC(c) alleles or achieved a partial repression of the high-constitutive rate of operon expression. Either mutation to a low-constitutive araC(c) mutant resulted in a partial or complete loss of repressor function, or subunit mixing between the two araC(c) mutant proteins resulted in a partial or complete dominance of the high-constitutive araC(c) allele. Five of the six araC(c) alleles tested allowed a partial induction of the ara operon in cya crp background. In general, a higher level of ara operon induction was achieved in the cya crp background by high araC(c) alleles than by low araC(c) alleles. Furthermore, several araC(c) mutants exhibited decreased sensitivity to catabolite repression, particularly in the presence of inducer. The results suggest a model in which certain araC(c) gene products can achieve ara operon induction in the presence of either arabinose (inducer) or catabolite activator protein-cyclic adenosine monophosphate, whereas the wild-type araC gene product requires the presence of both of these factors for operon expression.

Alleles↗
PubMed1975

Increased urinary excretion of nucleic acid and nicotinamide derivatives by rats after treatment with alkylating agents.

Rats treated with di(2-chloroethyl)methylamine (HN2), N-methyl-N-nitrosourea (MNUA) and N-ethyl-N-nitrosourea (ENUA) excrete significantly larger amounts of deoxycytidine (dC) and thymidine in their urine 0-24 h after treatment. Ethyl methanesulphonate (EMS) and dimethylnitrosamine (DMN) gave negative results in this respect but all five alkylating agents increased the excretion of 1-methyl-nicotinamide (1-meNmd). In addition, a larger quantity of 7-methylguanine (7MG) and uric acid was excreted after DMN treatment. 1,4-Dimethanesulphonoxybutane (myleran), 2,2-dichlorovinyl dimethyl phosphate (dichlorvos), 5-fluorouracil (5FU), cytosine arabinoside (araC), 2-acetylaminofluorene (AAF) and 7-bromomethylbenz-[a]anthracene (7-BrMBA) gave negative results.

2-Acetylaminofluorene↗
PubMed1977

Inhibition of DNA polymerase-alpha and -beta of calf thymus by 1-beta-D-arabinofuranosylcytosine-5'-triphosphate.

1-beta-D-Arabinofuranosylcytosine 5'-triphosphate (araCTP), an active form of a inhibitor of DNA replication, 1-beta-D-arabinofuranosylcytosine (araC) was tested for its inhibitory action on the DNA polymerase-alpha and -beta (EC 2.7.7.7) purified from calf thymus. The reaction of DNA polymerase-alpha was shown to be more sensitive to the inhibition by araCTP than that of DNA polymerase-beta. The mode of the inhibition by araCTP was competitive to dCTP in the reaction catalysed by either DNA polymerase-alpha or -beta. The Ki value of DNA polymerase-beta for araCTP was 32 micron; eight times higher than that of DNA polymerase-alpha (4 micron) for this inhibition.

Animals↗
PubMed1975

Cytosine arabinoside- and interferon-mediated control of polyoma and SV40 genome expression.

By metabolic DNA inhibitors such as araC, viral as well as host DNA replication is suppressed in polyoma- and SV40-infected cells. The interruption of the current viral DNA replication has no effect on the current transcription of the late viral genes. The persistence of the late transcription indicates that the onset, but not the persistence, of the viral DNA replication is a prerequisite for the persistence of the late polyoma and SV40 genome transcription. Pretreatment of monkey kidney cells with poly(I):-poly(C) nearly completely inhibits the SV40 T antigen formation; the early SV40 RNA formation is suppressed far less. This type of SV40 genome control favors the concept of a primary action of poly(I):poly(C)-mediated interference on SV40 translation.

Cell Line↗
PubMed1976

The lethality of aranucleotides.

Certain D-arabinosyl nucleosides, notably D-arabinosyl cytosine (araC) and D-arabinosyl adenine (araA), are useful in the treatment of certain leukemias and some DNA virus infections, respectively. The compounds are lethal to animal cells and some bacteria. Despite extensive deamination, the parent nucleosides are transported within sensitive cells and phosphorylated to the mono-, di- and triphosphates. AraCTP and araATP are good specific competitive inhibitors of tumor cell or virus-induced DNA polymerases, competing with dCTP and dATP, respectively. In addition to markedly inhibiting DNA synthesis, the aranucleotides enter newly formed DNA in internucleotide linkage. Sensitivity to the nucleosides appears to correlate with the relative ratio of formation of the triphosphate via a nucleoside kinase to degradation of the nucleoside via a nucleoside deaminase. Inhibition of the deaminase increases formation of the aranucleoside triphosphate in leukemic or virus-infected cells and markedly increases the toxicity of the nucleosides. Combinations of inhibitors of the deaminases and of the arnaucleoside are being explored in clinical situations. In addition, the slow penetration of aranucleotides into cells has been observed and some of these 5'-phosphates are useful antiviral agents, e.g. against herpes virus in herpetic keratitis.

Animals↗
PubMed1977

The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA).

Certain D-arabinosyl nucleosides, notably arabinosyl cytosine (araC) and arabinosyl adenine (araA), are useful in the treatment of certain leukemias and some DNA virus infections, respectively. The compounds are lethal to animal cells and some bacteria. Despite extensive deamination, the parent nucleosides are transported within sensitive cells and phosphorylated to the mono-, di- and triphosphates. AraCTP and araATP are good specific competitive inhibitors of tumor cell of virus-induced DNA polymerases, competing with dCTP and dATP respectively. In addition to markedly inhibiting DNA synthesis, the aranucleotides enter newly formed DNA in internucleotide linkage. Sensitivity to the nucleosides appears to correlate with the relative ratio of formation of the triphosphate via a nucleoside kinase to degradation of the nucleoside via a nucleoside deaminase. Inhibition of the deaminase increases formation of the aranucleoside triphosphate in leukemic or virus-infected cells and markedly increases the toxicity of the nucleosides. Combinations of inhibitors of the deaminases and of the aranucleoside are being explored in clinical situations. In addition, the slow penetration of aranucleotides into cells has been observed and some of these 5'-phosphates are useful antiviral agents, e.g., against herpes virus in herpetic kiratitis.

Adenine↗
PubMed1977

The immunotherapy of acute myelogenous leukaemia using intravenous BCG.

In a 2-year period, 37 of 81 adults with acute myelogenous leukaemia achieved complete remission after repeated courses of Daunorubicin (DNR) and Cytosine Arabinoside (ARAC). They were randomized to maintenance treatment with monthly DNR/ARAC, or to identical chemotherapy plus intravenous BCG. Eighteen BCG treated patients had significantly longer survival times than 19 patients treated with chemotherapy only although no statistically significant difference can be seen in the remission duration of the two groups. Eleven patients in the BCG treated group who have relapsed, have received DNR/ARAC reinduction and five second and two third remissions have been obtained. Twelve control group patients have relapsed and 10 have received further reinduction treatment with DNR/ARAC but only one patient has entered a complete remission. Seven patients in the BCG treated group who survived for 75 weeks or more (76, 76, 96, 124, 125, 138 and 145 weeks) were either PPD positive before treatment or converted to PPD positivity after BCG treatment. Using a battery of skin tests it may be possible to define a good prognostic group of patients and design future treatment accordingly. The BCG group had a total of 198 intravenous treatments. All patients had pyrexia 6-12 h after injection lasting 12-72 h and occasionally headaches and muscle pains. Two patients had non-fatal anaphylactic reactions which did not recur when BCG was subsequently re-administered. Other complications of BCG therapy were not a problem and we have not needed to withdraw treatment for any patient.

Acute Disease↗