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Biomedical subjects

J J Fox

Publications and source records attributed to J J Fox.

At least 55 records · Page 3Linked to original sources
PubMed1983

Phase I evaluation of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine in immunosuppressed patients with herpesvirus infection.

2'-Fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC) is a potent selective inhibitor of the replication of herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella zoster virus, and cytomegalovirus in cell culture systems. FIAC produces an unequivocal therapeutic effect in mice that have been inoculated with a lethal burden of HSV-1. We have administered FIAC to 32 host compromised patients, 30 with advanced cancer, who were experiencing acute herpesvirus infections (varicella zoster, 29; HSV-1, 2; HSV-2, 1); the drug was given by 20 min i.v. infusion twice a day for 7 days. The dosage levels explored were 60, 120, 240, 400, and 600 mg/sq m/day. Drug-induced myelosuppression became evident at 600 mg/sq m/day; thrombocytopenia exceeded leukopenia. The toxic low dose was 400 mg/sq m/day with mild nausea and rare myelosuppression. All 24 varicella zoster patients with cutaneous disease receiving FIAC, greater than or equal to 120 mg/sq m/day, experienced stabilization of cutaneous lesions within 48 to 72 hr; healing began promptly thereafter.

Antiviral Agents↗
PubMed1982

Quantitative autoradiographic mapping of herpes simplex virus encephalitis with a radiolabeled antiviral drug.

2'-Fluoro-5-methyl-l-beta-D-arabinosyluracil (FMAU) labeled with carbon-14 was used to image herpes simplex virus type 1-infected regions of rat brain by quantitative autoradiography. FMAU is a potent antiviral pyrimidine nucleoside which is selectively phosphorylated by virus-coded thymidine kinase. When the labeled FMAU was administered 6 hours before the rats were killed, the selective uptake and concentration of the drug and its metabolites by infected cells (defined by immunoperoxidase staining of viral antigens) allowed quantitative definition and mapping of HSV-1-infected structures in autoradiograms of brain sections. These results show that quantitative autoradiography can be used to characterize the local metabolism of antiviral drugs by infected cells in vivo. They also suggest that the selective uptake of drugs that exploit viral thymidine kinase for their antiviral effect can, by appropriate labeling, be used in conjunction with clinical neuroimaging techniques to define infected regions of human brain, thereby providing a new approach to the diagnosis of herpes encephalitis in man.

Animals↗
PubMed1982

C(2')-substituted purine nucleoside analogs. Interactions with adenosine deaminase and purine nucleoside phosphorylase and formation of analog nucleotides.

Four C(2')-substituted 2'-deoxyadenosines were examined as substrates for human erythrocytic adenosine deaminase and for formation of intracellular nucleotide analogs in human erythrocytes, lymphocytes and murine Sarcoma 180 cells: 9-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)adenine, 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)adenine, 9-(2'-azido-2'-deoxy-beta-D-ribofuranosyl)adenine (2'-N3-riboA) and 9-(2-azido-2'-deoxy-beta-D-arabinofuranosyl)adenine. All four adenosine analogs were substrates of human erythrocytic adenosine deaminase, but the corresponding inosine analogs (synthesized by the adenosine deaminase reaction) were highly resistant to cleavage by human erythrocytic purine nucleoside phosphorylase. Only 9-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)hypoxanthine underwent very slow phosphorolysis, and no inhibition of inosine phosphorolysis was detected when a 30 microM concentration of any studied inosine analog was added to a reaction mixture containing 30 microM inosine (the Km concentration). Kinetic parameters were determined for the deamination of the adenosine analogs. The greatest affinity for adenosine deaminase was found with 2'-N3-ribo A (Ki = 2 microM), but the reaction velocity was highest with the F-substituted analogs. All four adenosine analogs formed triphosphate nucleotides after incubation with human erythrocytes, murine Sarcoma 180 cells, or human lymphocytes (tested only with the F analogs) in the presence of deoxycoformycin.

Adenosine Deaminase↗
PubMed1982

Incorporation of metabolites of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine into deoxyribonucleic acid of neoplastic and normal mammalian tissues.

The radioactivity of 14C-labeled 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine ([2-14C]-FIAC), a new and potent antiherpetic agent, was shown previously to be incorporated into the DNA fractions of mammalian and neoplastic tissues. The present work was undertaken to learn the nature of the incorporated moieties. Enzyme degradation of highly purified DNA from the small intestine of mice treated with [2-14C]FIAC and analysis of the resulting nucleosides failed to reveal the presence of unchanged FIAC. Rather, three metabolites were found, namely, the 2'-fluoro-1-beta-D-arabinofuranosyl nucleosides of cytosine (FAC), thymine (FMAU) and 5-iodouracil (FIAU). Labeled metabolites of FIAC were also found in the DNA isolated from P815 leukemic cells in mice given [2-14C]FIAC. It is of interest to note that FMAU, FIAU and FAC are, like FIAC, potent antiherpetic agents.

Animals↗
PubMed1982

Synthesis of 3-methylpseudouridine and 2'-deoxy-3-methyl-pseudouridine.

The first chemical synthesis of 3-methyl-psi-uridine (5) and its 2'-deoxy analogue (9) has been achieved. psi-Uridine was trimethylsilylated and the crude product was treated with acetyl chloride, to give the 1-acetyl derivative (3). Crude 3 was methylated with dimethoxymethyldimethylamine and then saponified, to give crystalline 5 in 82% overall yield. Treatment of 5 with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane afforded the 3'5'-protected product, which was converted into the 2'O-[(imidazol-1-yl) thiocarbonyl] derivative 7. Reduction of 7 with tributyltin hydride followed by deblocking of the product gave crystalline 2'-deoxy-3-methyl-psi-uridine (9) in 35% yield form 5.

Indicators and Reagents↗
PubMed1982

Activity of 2-fluoro-5-methylarabinofuranosyluracil against mouse leukemias sensitive to and resistant to 1-beta-D-arabinofuranosylcytosine.

A new pyrimidine nucleoside, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil, previously has been shown to be active against the herpes group of viruses in vitro and in vivo. It is also active against mouse and human leukemic cells in culture and against mouse leukemias L1210, P388, and P815 in vivo. In contrast to other 1-beta-D-arabinofuranosylcytosine (ara-C) derivatives, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil, when given either i.p. or p.o., is highly active against lines of leukemias P815 and L1210 made resistant to ara-C. Against P815/ara-C and L1210/araC, it is more effective than is 5-azacytidine, a drug which has shown definite effectiveness in patients with acute leukemia whose disease has become resistant to ara-C. For these reasons, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil would seem to merit clinical trial in patients with acute nonlymphocytic leukemia whose disease has become resistant to ara-C.

Animals↗
PubMed1981

Nucleosides. 114. 5'-O-Glucuronides of 5-fluorouridine and 5-fluorocytidine. Masked precursors of anticancer nucleosides.

5'-O-Glucuronides of anticancer nucleosides, 5-fluorouridine and 5-fluorocytidine, were synthesized by three different methods. The best preparative procedure was the one starting from benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-2,3-O-isopropylidene-beta-D-ribof uranoside (15) that was obtained almost quantitatively by condensation of benzyl 2,3-O-isopropylidene-beta-D-ribofuranoside (8) with methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl bromide)uronate (2). After de-O-isopropylidenation of 15, the crystalline product, benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-beta-D-ribofuranoside (16), was de-O-benzylated catalytically to 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-glucopyranosyluronate)-D-ribofuranose (17). Compound 17 was acetylated to crystalline 5-O-(methyl 2',3',4'-tri-O-acteyl-beta-D-glucopyranosyluronate)-1,2,3-tri-O-acetyl-beta-D-ribofuranose (18) and condensed with trimethylsilylated 5-fluorouracil of 5-fluorocytosine in the presence of SnCl4 to afford the corresponding protected nucleosides 5 and 19 in good yields. Saponification of these compounds gave 5'-O-beta-D-glucuronides of 5-fluorouridine and 5-fluorocytidine (20 and 21) isolated as their crystalline N salts. These glucuronides were substrates of both bacterial and bovine beta-glucuronidase. They were, as expected, much less toxic against several leukemia cell lines in tissue culture.

Antineoplastic Agents↗
PubMed1981

Differential activity of potential antiviral nucleoside analogs on herpes simplex virus-induced and human cellular thymidine kinases.

Potential antiviral nucleoside analogs 1-beta-D-arabinofuranosylthymine, the 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-nucleosides of -5-methyluracil, -5-iodouracil, -5-methylcytosine, -5-iodocytosine, and -E-5-(2-bromovinyl)uracil, E-5-(2-bromovinyl)-2'-deoxyuridine, E-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil, and 9-(2-hydroxyethyoxymethyl)guanine were studied to compare their phosphorylation rates relative to thymidine by purified thymidine kinases from human and herpes simplex virus sources. Most of these analogs are capable of being phosphorylated by both human and viral enzymes. On the assumption that inhibition constants (Ki) reflect binding affinity, Ki values were determined for these analogs with the same thymidine kinases. In general, these analogs have a greater affinity for the viral enzymes. The amount of the analogs phosphorylated to the monophosphate form, which is presumably necessary to produce cytotoxic effects, was determined by the combined effects of phosphorylation rates and binding affinities. All of these analogs act as preferential substrates for the viral thymidine kinases at low concentrations, which may be one of the main reasons for their selective antiviral action.

Antiviral Agents↗
PubMed1981

Setting events in applied behavior analysis: Toward a conceptual and methodological expansion.

The contributions of applied behavior analysis as a natural science approach to the study of human behavior are acknowledged. However, it is also argued that applied behavior analysis has provided limited access to the full range of environmental events that influence socially significant behavior. Recent changes in applied behavior analysis to include analysis of side effects and social validation represent ways in which the traditional applied behavior analysis conceptual and methodological model has been profitably expanded. A third area of expansion, the analysis of setting events, is proposed by the authors. The historical development of setting events as a behavior influence concept is traced. Modifications of the basic applied behavior analysis methodology and conceptual systems that seem necessary to setting event analysis are discussed and examples of descriptive and experimental setting event analyses are presented.

Journal Article↗
PubMed1981

Evaluation of the antiherpetic activity of 2'-fluoro-5-iodo-ara-C in rabbit eyes and cell cultures.

2-Fluoro-5-iodo-ara-C (FIAC), a new and potent drug, was tested for antiviral activity against several strains of herpes simplex virus (HSV), types 1 and 2. Effective dose-50% (ED-50) determinations for FIAC ranged from 0.023 to 0.51 muM for HSV-2. FIAC-treated cells did not exhibit any toxicity until the drug concentration was increased 2000-fold above the ED-50 level. Ocular herpetic keratitis in New Zealand white rabbits was treated with 1.0%, 0.1%, 0.01% FIAC beginning 3 days after inoculation wit HSV-1 (McKrae strain). Topical chemotherapy was administered five times per day for 7 consecutive days. After 4 days of treatment, corneal epithelial involvement, conjunctivitis, iritis, and clouding were not detectable in eyes receiving 1.0% FIAC. Toxic reactions were not observed in rabbit eyes treated with FIAC drug. HSV was not prevented from spreading into the central nervous system when topical FIAC therapy was initiated on day 3 after inoculation.

Animals↗
PubMed1980

Nucleosides. 116. 1-(beta-D-Xylofuranosyl)-5-fluorocytosines with a leaving group on the 3' position. Potential double-barreled masked precursors of anticancer nucleosides.

Syntheses of five pairs of cytosine and 5-fluorocytosinexylofuranosyl nucleosides in which the 3'-hydroxyl group is replaced by Cl, Br, OMs, or OTs are described. Those xylosyl nucleosides with a good leaving group at the 3' position exhibit good inhibitory activity against L5178Y and P815 mouse leukemic cells in vitro at rather low concentrations, and like that of ara-C this cytotoxicity is reversed by 2'-deoxycytidine but not by thymidine. Xylosylcytosines are not active against ara-C resistant lines of L5178Y and P815 cells; however, the corresponding 5-fluorocytosine analogues exhibit significant cytotoxicity against these ara-C resistant leukemic cell lines, and this activity is reversed by thmidine but not by deoxycytidine. These data support the "double-barreled" masked precursor hypothesis in that xylosyl-5-fluorocytosines substituted at the 3' position by a good leaving group exhibit activity akin to that of ara-C in the ara-C sensitive lines, while these nucleosides act as 5-fluoropyrimidines in the ara-C resistant lines.

Animals↗