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Biomedical subjects

G B Elion

Publications and source records attributed to G B Elion.

At least 91 records · Page 5Linked to original sources
PubMed1980

Modulation of cyclic AMP metabolism by S-adenosylhomocysteine and S-3-deazaadenosylhomocysteine in mouse lymphocytes.

Mouse lymphocytes incubated with micromolar concentrations of adenosine or 3-deazaadenosine, in medium supplemented with L-homocysteine, rapidly accumulated supramillimolar concentrations of S-adenosylhomocysteine (AdoHcy) or S-3-deazaadenosylhomocysteine (c3AdoHcy), respectively. Lymphocytes thus preloaded with high levels of AdoHcy or c3AdoHcy exhibited markedly enhanced (5- to 40-fold) cyclic AMP responses to prostaglandin E1, adenosine, 2-chloroadenosine, isoproterenol, and cholera toxin. This enhancement of cyclic AMP response by intracellular AdoHcy or c3AdoHcy was attributable both to amplification of the activity of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and to inhibition of cyclic AMP phosphodiesterase (3',5'-cyclic-nucleotide 5'-nucleotidohydrolase, EC 3.1.4.17). Basal and prostaglandin E1- and isoproterenol-stimulated activities of adenylate cyclase, assayed in lymphocyte homogenates, were increased 1.3- to 2.0-fold after treatment of the cells with homocysteine plus either adenosine or 3-deazaadenosine. AdoHcy and c3AdoHcy were found to be competitive inhibitors (with Ki values of 1.7 and 4.8 mM, respectively) of the high-affinity cyclic AMP phosphodiesterase present in lymphocyte homogenates. It is evident, therefore, that increased cellular levels of AdoHcy or c3AdoHcy can affect cellular physiology via perturbation of cyclic AMP metabolism as well as via inhibition of S-adenosylmethionine-dependent methylation reactions.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1980

In vitro susceptibility of varicella-zoster virus to acyclovir.

The in vitro susceptibility of five strains of varicella-zoster virus to acyclovir was examined by the plaque-reduction method in human diploid lung cells. The 50% effective doses of acyclovir ranged from 2.06 microM to 6.28 microM in a 7-day assay, with a mean of 3.65 microM. Irreversible inhibition of plaque formtation was achieved by drug doses exceeding the 50% effective dose for plaque reduction but nontoxic to the cells. Studies on the relative in vitro susceptibility of varicella-zoster virus and herpes simplex virus types 1 and 2 to acyclovir suggested that varicella-zoster virus is two- to eightfold less susceptible to the drug. The antiviral potency of acyclovir for varicella-zoster virus in vitro was compared with that of several other nucleoside analogs. Analysis of the metabolism of acyclovir in varicella-zoster virus-infected WI-38 cells revealed that, as with herpes simplex virus types 1 and 2, the formation of the triphosphate forms of the drug is specific to viral infection.

Acyclovir↗
PubMed1980

Inhibition of cellular alpha and virally induced deoxyribonucleic acid polymerases by the triphosphate of acyclovir.

The effect of the triphosphate of 9-(2-hydroxyethoxymethyl)guanine (acyclovir, acycloguanosine) on cellular alpha deoxyribonucleic acid (DNA) polymerases (DNA nucleotidyltransferases), DNA polymerases of several members of the herpes group, vaccinia virus DNA polymerase, and Friend leukemia virus ribonucleic acid-dependent DNA polymerase was examined. Several viruses, which were found to be susceptible to acyclovir, were found to induce DNA polymerases which were sensitive to acyclovir triphosphate (acyclo-GTP). Human cytomegalovirus and the H29R strain of herpes simplex virus type 1, however, were found to be relatively insusceptible to acyclovir, even though their induced DNA polymerases were inhibited by low concentrations of acyclo-GTP. The amount of acyclovir anabolized to acyclo-GTP was significantly lower for human cytomegalovirus and H29R than for the more susceptible viruses. Vaccinia virus and Friend leukemia virus induced DNA polymerases which were insensitive to inhibition by low concentrations of acyclo-GTP, anabolized little acyclovir to acyclo-GTP, and were found to be insensitive to inhibition by acyclovir. Uninfected WI-38 cells were not susceptible to inhibition by acyclovir, anabolized little acyclovir to acyclo-GTP, and had an alpha DNA polymerase which was insensitive to inhibition by low concentrations of acyclo-GTP.

Acyclovir↗
PubMed1980

Effect of acyclovir [9-(2-hydroxyethoxymethyl)guanine] on Epstein-Barr virus DNA replication.

The effect of acyclovir [9-(2-hydroxyethoxymethyl)guanine] on Epstein-Barr virus (EBV) DNA replication in the lymphoblastoid cell lines P3HR-1 and Raji is reported. Acyclovir at a concentration of 100 microM completely inhibited EBV DNA synthesis in superinfected Raji cells, but did not inhibit DNA synthesis in mock-infected cells. The number of EBV genome equivalents per cell in the virus-producing cell line P3HR-1 was significantly reduced by acyclovir, whereas the number of latent EBV genomes in Raji cells was not affected by the drug. In situ cytohybridization performed on untreated P3HR-1 cultures revealed the presence of relatively large amounts of EBV DNA in 15 to 20% of the cells. After a 100 microM drug treatment, no P3HR-1 cells contained levels of EBV DNA detectable by in situ cytohybridization. Indirect immunofluorescence studies demonstrated that during treatment with 100 microM acyclovir for 7 days, the percentage of P3HR-1 cells expressing viral capsid antigen was reduced. The EBV DNA remaining in P3HR-1 cells after treatment with 100 microM acyclovir (approximately 14 genomes per cell) had the properties of covalently closed circular DNA with an average molecular weight of 108 X 10(6), as determined by contour length measurements.

Acyclovir↗
PubMed1979

Metabolism of pyrazolo(3,4-d)pyrimidines in Leishmania braziliensis and Leishmania donovani. Allopurinol, oxipurinol, and 4-aminopyrazolo(3,4-d)pyrimidine.

Leishmania donovani and Leishmania braziliensis grown in culture formed millimolar concentrations of allopurinol ribonucleoside 5'-monophosphate from [6-14C]allopurinol. In addition, allopurinol 1-ribonucleoside, oxipurinol riboside 5'-monophosphate, and three new metabolites of allopurinol, namely, 4-aminopyrazolo(3,4-d)pyrimidine ribonucleoside 5'-monophosphate and the corresponding di- and triphosphates (1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-diphosphate and 1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-triphosphate) were identified in the parasitic cells. They were formed via a unique amination reaction from 1-ribosyl allopurinol 5'-phosphate, analogous to the conversion of IMP to AMP. [6-14C]Allopurinol was incorporated into RNA of L. donovani in the form of 4-aminopyrazolo(3,4-d)pyrimidine. Adenine reversed the growth inhibition of allopurinol and prevented its metabolism to all of the ribonucleotide metabolites. L. donovani was 2- to 4-fold more active in its metabolism of allopurinol to ribonucleotides than L. braziliensis. 4-Aminopyrazolo(3,4-d)pyrimidine inhibited cell growth and resulted in high intracellular levels of 1-ribosyl allopurinol 5'-phosphate and smaller amounts of the 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides. The metabolism of allopurinol to 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides and its resultant cytotoxicity occurs in these parasitic protozoans, but not in mammalian cells.

Adenine↗
PubMed1979

Acyclovir kinetics after intravenous infusion.

The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

Aged↗
PubMed1979

Comparative metabolism of a new antileishmanial agent, allopurinol riboside, in the parasite and the host cell.

HPP-Rib is a potent antileishmanial agent, which has been useful in defining new and unusual purine metabolizing pathways in leishmaniae, in comparison with those in the host. The ribosyl linkage both in the parasite and in the host is resistant to cleavage. In the parasite there is a selective and marked conversion of HPP-Rib to HPP-Rib-5'-P and 4-APP ribonucleotides as well as incorporation into RNA, which does not occur in the host. These findings with HPP-Rib suggest a new chemotherapeutic approach which may be exploited in the treatment of leishmaniasis.

Allopurinol↗
PubMed1979

Effect of acycloguanosine treatment of acute and latent herpes simplex infections in mice.

Systemic treatment of mice with the nucleoside analog 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine [aciclovir]) was found to be highly effective against acute type 1 herpes simplex virus infection of the pinna. The drug ablated clinical signs and reduced virus replication both in tissue local to the inoculation site and within the nervous system. Provided that moderate-sized virus inocula were used, acycloguanosine treatment reduced or prevented the establishment of a latent infection in the dorsal root ganglia relating to the sensory nerve supply of the ear. However, although it aborted artificially produced infections in dorsal root ganglia, acycloguanosine was found not to be effective against the latent infection once established. This finding strongly indicated that latent herpes simplex virus in mice can exist in a nonreplicating form.

Animals↗
PubMed1979

Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate.

The effect of the nucleoside analog 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) on herpes simplex virus type 1 DNA synthesis was examined. Acycloguanosine inhibited herpesvirus DNA synthesis in virus-infected cells. The synthesis of host cell DNA was only partially inhibited in actively growing cells at acycloguanosine concentrations several hundred-fold greater than the 50% effective dose for herpes simplex virus type 1. Studies using partially purified enzymes revealed that the triphosphate of this compound inhibited the virus-induced DNA polymerases (DNA nucleotidyltransferases) to a greater degree than the DNA polymerase of the host cell, that the inhibition was dependent upon the base composition of the template, and that the triphosphate was a better substrate for the virus-induced polymerases than for the alpha cellular DNA polymerases.

Animals↗
PubMed1977

Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine.

A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED(50)) = 0.1 muM] against herpes simplex virus type 1. This acyclic nucleoside analog, termed acycloguanosine, is converted to a monophosphate by a virus-specified pyrimidine deoxynucleoside (thymidine) kinase and is subsequently converted to acycloguanosine di- and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited extent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerase. These factors contribute to the drug's selectivity; inhibition of growth of the host cell requires a 3000-fold greater concentration of drug than does the inhibition of viral multiplication. There is, moreover, the strong possibility of chain termination of the viral DNA by incorporation of acycloguanosine. The identity of the kinase that phosphorylates acycloguanosine was determined after separation of the cellular and virus-specified thymidine kinase activities by affinity chromatography, by reversal studies with thymidine, and by the lack of monophosphate formation in a temperature-sensitive, thymidine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsA1).

Antiviral Agents↗