Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sequential isolates of herpes simplex virus type 1 (HSV-1) from a child with severe combined immunodeficiency were examined for sensitivity to acyclovir. Early intravenous courses of acyclovir resulted in dramatic clinical improvement and were associated with the isolation of sensitive strains of HSV-1 (ID50[dose inhibiting 50% of control plaques], 0.010-0.106 microgram/ml), whereas later recurrences following intravenous, oral, and ophthalmic therapy were characterized by low-grade chronic lesions (ID50, 1.04-9.43 microgram/ml) that were unresponsive to acyclovir despite serum levels of up to 10.45 microgram/ml. Diminished sensitivity was associated with reduced viral thymidine kinase activity, and linked resistance with idoxuridine was detected in the isolates from the patient's eye. Intracerebral and cutaneous snout inoculation of a resistant isolate into BALB/c, hairless, and athymic nude mice revealed a 100- to 1,000-fold decrease in virulence as compared with an early sensitive isolate. Acyclovir-resistant HSV-1 can emerge in certain clinical settings but may be associated with diminished virulence.
...
PMID:Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an immunodeficient child. 629 May 75

The nature of the defect of a female baby who died of severe combined immunodeficiency (SCID) disease associated with adenosine deaminase deficiency (ADA-) was investigated. Since tissue or tissue culture material was not available for subsequent studies, the expression of ADA in her cells was investigated in the somatic cell hybrid clones derived from a fusion between the lymphocytes from one of her two obligate heterozygote parents and thymidine kinase deficient Chinese hamster (a3) fibroblasts. The results of analyses of the human chromosomes and biochemical markers in 12 independent clones and 27 subclones indicated that the ADA deficiency in the patient is determined probably by a mutation in the structural gene for ADA in chromosome 20 leading either to the production of catalytically defective molecules or to the cessation of the production of ADA. Incidentally, the involvement of chromosome 2, which carries a gene for adenosine deaminase complexing protein (ADCP), in the causation of ADA deficiency was excluded. The in vitro approach through the cells from an obligate heterozygote described in this paper may have a general application in pursuing studies on other cases of inborn errors of metabolism whenever the material from the affected individuals (i.e., the homozygotes) is not available or not suitable for direct investigations.
...
PMID:Basic defect in the expression of adenosine deaminase in ADA- SCID disease investigated through the cells of an obligate heterozygote. 723 21

We describe the mutagenesis of the IRSI-US5 region of the human cytomegalovirus genome, demonstrating the potential of the E. coli guanosine phosphoribosyl transferase (gpt) gene as a selectable marker for insertion and deletion mutagenesis of high passage (AD169, Towne) as well as low passage (Toledo) strains of virus. Despite evidence suggesting that the US3 gene product may play a regulatory role, disruption of this gene with a gpt insert had no effect on growth of any of these strains of virus in resting or dividing human fibroblasts, or in human thymus plus liver implants in SCID-hu mice. Transcripts of the gpt gene, under control of the herpes simplex virus thymidine kinase promoter adjacent to the US3 enhancer in the viral genome, accumulated with delayed early (beta) kinetics. Mutants with deletions in the IRS1 and US3-US5 regions were isolated by back-selection against gpt with the drug 6-thioguanine by growing virus in human Lesch-Nyhan (hypoxanthine-guanine phosphoribosyl transferase deficient) skin fibroblasts immortalized with human papillomavirus oncogenes. Thus, we demonstrate a dependable method for insertion and deletion mutagenesis that can be applied to any region of the viral genome.
...
PMID:Selectable insertion and deletion mutagenesis of the human cytomegalovirus genome using the Escherichia coli guanosine phosphoribosyl transferase (gpt) gene. 756 52

The efficacy of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) was evaluated in several animal models for herpesvirus infections. Compound S2242 was more effective than acyclovir (i) when administered subcutaneously in a model for herpes simplex virus type 1 (HSV-1)-induced mortality in immunocompetent mice and (ii) when applied topically to hairless (hr/hr) mice that had been infected intracutaneously with HSV-2. In SCID (severe combined immune deficient) mice that had been infected with a thymidine kinase-deficient HSV-1 strain, S2242 (administered subcutaneously at a dosage of 50 mg/kg/day) completely protected against virus-induced mortality whereas foscarnet was less effective and acyclovir had no or little protective effect. Compound S2242 was far more effective than ganciclovir in preventing or delaying murine cytomegalovirus-induced mortality in immunocompetent and SCID mice. The compound was more effective when a given dose was fractionated and administered on subsequent days than when this dose was administered in one single injection. A 5-day treatment course with S2242 (10 and 50 mg/kg/day) for newborn mice that had been infected with a lethal dose of murine cytomegalovirus suppressed virus-induced mortality. Compound S2242 had no inhibitory effect on the growth of weanling (at 50 mg/kg for 5 days) and 3- to 4-week-old mice (at doses of 50 to 200 mg/kg for 6 weeks). However, akin to ganciclovir, compound S2242 significantly reduced testicle weight, testicle morphology, and spermatogenesis.
...
PMID:In vivo antiherpesvirus activity of N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine. 769 29

The use of retroviral-mediated gene transfer to introduce a DNA label into T cells (TIL) being used in the immunotherapy of patients with malignant melanoma finally opened the door to the clinical application of gene therapy for a wide variety of inherited and acquired diseases. The gene therapy trial for ADA deficiency SCID has demonstrated that long term stable expression of exogenous genes can be achieved in human T lymphocytes using retroviral vectors for ex vivo treatment and that significant immune reconstitution can be achieved in these patients following periodic infusions with ADA gene-corrected autologous T cells. Newer clinical applications include the insertion of genes into CD34 enriched stem cell populations, the testing of autologous tumor vaccines employing cytokine gene-modified tumor cells and the direct transfer of the herpes thymidine kinase gene into brain tumors in situ in order to render those tumors sensitive to treatment with the ordinarily non-cytotoxic drug ganciclovir.
...
PMID:Strategies for gene therapy. 829 Mar 10

An isosteric analog of 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG), 9-[[(ethoxyhydroxyphosphinyl)methoxy]methoxy]guanine (SKI 1008), was evaluated for its in vitro antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), murine cytomegalovirus (MCMV), and human cytomegalovirus (HCMV), and its in vivo antiviral efficacy against MCMV in mice. The in vitro anti-HSV activity of SKI 1008 was much lower than that of acyclovir, even though SKI 1008 showed similar antiviral activity against thymidine kinase positive (TK+) and thymidine kinase negative (TK-) strains. Like ganciclovir and PMEG, SKI 1008 selectively inhibited plaque formation of MCMV; the 50% effective concentration (EC50) and the 50% cytotoxic concentration (CC50) of SKI 1008, ganciclovir, and PMEG being 0.51 and 600, 1.65 and 461, and 0.06 and 12.1 micrograms/ml, respectively. The in vitro EC50 value of SKI 1008 against HCMV was comparable to that of ganciclovir (0.24 vs 0.16 microgram/ml) and was 12-fold higher than that of PMEG in a plaque reduction assay, but the therapeutic indices (the ratios of CC50 to EC50) of SKI 1008 and ganciclovir were higher than that of PMEG. The in vivo antiviral efficacy of SKI 1008 in MCMV-infected normal BALB/c and severe combined immunodeficiency (SCID) mice was lower than that of ganciclovir in terms of mortality and mean survival time.
...
PMID:Antiviral activity of 9-[[(ethoxyhydroxyphosphinyl)-methoxy]methoxy] guanine against cytomegalovirus and herpes simplex virus. 862 16

Collagen-induced arthritis can be transferred into severe combined immunodeficiency (SCID) mice by spleen cells from diseased DBA/1 mice. The development of arthritis in SCID animals can be prevented by infection ex vivo of DBA/1 spleen cells with retroviruses expressing the monomeric soluble human p75 tumor necrosis factor (TNF) receptor (TNF-R). In addition, a vector engineered to express a polycystronic mRNA with TNF-R and the herpes simplex virus thymidine kinase (HSVtk) gene, while producing low levels of TNF-R, had a limited effect which could be blocked by treating the animals with ganciclovir. A retroviral vector expressing the HSVtk gene alone had no effect on this arthritis transfer model with or without ganciclovir. Serum levels of TNF-R did not correlate with clinical signs, however, lower anti-collagen antibody levels corresponded with lack of clinical symptoms. These results indicate that local production of cytokine inhibitor is essential for therapeutic purposes while systemic levels may not be required.
...
PMID:Inhibition of transfer of collagen-induced arthritis into SCID mice by ex vivo infection of spleen cells with retroviruses expressing soluble tumor necrosis factor receptor. 875 12

The development of an effective vaccine for human immunodeficiency virus type 1 (HIV-1) would be a major advance toward controlling the AIDS pandemic. Several disparate strategies for a safe and effective HIV vaccine have been proposed. Recent data suggest that loss-of-function live-attenuated virus could be a safe lentivirus vaccine. Here, we propose a gain-of-function approach that can complement loss-of-function in enhancing the safety profile of a live-attenuated virus. We describe an example in which ganciclovir (GCV) was used to treat effectively nef(-)HIV-1 engineered to express herpes simplex virus (HSV-1) thymidine kinase (TK). This treatment was found to be highly efficient in controlling HIV-1 spread in tissue culture and in a small animal (hu-PBL-SCID) model. We demonstrate that one distinct advantage of GCV-HSV-TK treatment is the elimination of integrated proviruses, a goal not easily achieved with other antiretrovirals.
...
PMID:Conditional reduction of human immunodeficiency virus type 1 replication by a gain-of-herpes simplex virus 1 thymidine kinase function. 875 84

The herpes simplex virus thymidine kinase gene is the most widely utilized toxin for selective killing of carcinoma cells. Expression of the viral thymidine kinase gene renders cells sensitive to the toxic effects of nucleoside analogs such as ganciclovir. An advantage of this system is the "bystander effect" whereby thymidine kinase transduced tumor cells elicit a toxic effect on surrounding nontransduced tumor cells. Ovarian carcinoma appears to be an ideal candidate for gene therapy as the majority of women present with advanced stage disease, have poor prognosis for long-term survival and have the disease confined within the peritoneal cavity. Therefore the utility of an adenoviral vector to elicit an in vitro bystander effect in ovarian carcinoma cells and the therapeutic efficacy of such a system in vivo was undertaken. Immunocompetent animals were utilized to determine the maximum dose of adenovirus that could be administered without any undesirable side effects and that preimmunization had no effects on subsequent challenge. SCID mice were orthotopically transplanted with human ovarian carcinoma cells and, after establishment of tumor, given a recombinant adenovirus expressing either the herpes simplex virus thymidine kinase or the Escherichia coli beta-galactosidase gene. Half the animals from each viral group were treated with either a ganciclovir regiment (50 mg/kg daily for 14 days) or an equal volume of serum-free media. A subset of mice were killed following drug treatment and analyzed for tumor reduction. The remaining animals were followed daily for survival. The animals treated with the recombinant adenovirus expressing the herpes simplex virus thymidine kinase gene and ganciclovir had significant reduction in overall tumor burden and demonstrated statistically significant prolongation in overall survival.
...
PMID:Adenoviral-mediated delivery of herpes simplex virus thymidine kinase results in tumor reduction and prolonged survival in a SCID mouse model of human ovarian carcinoma. 887 59

Genetic alterations in malignant tissues are potential targets for gene-based cancer therapies. Alternatively, aberrant expression of certain specific genes associated with malignant transformation may be envisioned to enhance the expression of chemosensitizing drugs. Epstein-Barr virus (EBV)-related B-cell lymphomas are fatal complications of immunosuppression due to AIDS, organ transplantation or congenital immune abnormalities. The malignant cells latently infected with EBV typically express the transcription factor EBNA2 as one of nine latent viral genes. We tested whether an EBNA2-responsive EBV promoter may selectively target EBV-related lymphoma cells by virus-regulated expression of a suicide gene. Using the BamC promoter driving a hygromycin-thymidine kinase fusion gene or controls, we demonstrated that sensitivity to ganciclovir was selectively enhanced in cells expressing EBNA2. Further, there was complete macroscopic regression of established B-cell lymphomas in mice with severe combined immunodeficiency disease (SCID mice) treated with a single course of ganciclovir. These data provide in vitro and in vivo support for a model of exploiting the molecular basis of tumor development to enhance the specificity of gene therapy.
...
PMID:Epstein-Barr virus-driven gene therapy for EBV-related lymphomas. 894 40


1 2 3 4 5 Next >>

---