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

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Query: UMLS:C0038362 (stomatitis)
8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A Phase I clinical trial of N-(phosphonacetyl)-L-aspartate, an antimetabolite which inhibits a key enzyme in the de novo pathway of pyrimidine biosynthesis, was conducted. N-(Phosphonacetyl)-L-aspartate was given as an i.v. 15-min infusion once daily for five days; cycles of treatment were repeated every three weeks. Thirty-four patients received treatment. Dose-limiting toxicity was observed at 1500 to 2000 mg/sq m/day and was manifested by skin rash, diarrhea, and stomatitis. Rash and diarrhea usually began during the first week of treatment and persisted up to Day 17 of a cycle of therapy. No consistent hematopoietic, hepatic, or renal toxicity was observed. One partial response in a patient with colon carcinoma was seen and continues at more than eight months. Stable disease was observed in three patients with colon carcinoma, two patients with hypernephroma, one patient with pancreatic carcinoma, and one patient with melanoma. The predictability and reversibility of toxicity and the suggestion of antitumor activity in humans are observations which support the further evaluation of N-(phosphonacetyl)-L-aspartate in Phase II studies.
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PMID:Phase I trial of N-(phosphonacetyl)-L-aspartate. 15 1

In order to evaluate the influence of the cyano group on the antiviral activity of pyrimidine deoxyribonucleosides, a moderate yield, unified approach to the synthesis of both 5-cyanouridine and 5-cyano-2'-deoxyuridine was developed. Thus, treatment of the appropriate acetylated 5-bromouracil nucleoside with NaCN or KCN in Me2SO at 90-110 degrees C gave, after deblocking, 35-45% yields of the corresponding 5-cyanouracil nucleosides. 5-Cyanouridine was devoid of significant activity against vaccinia virus, herpes simplex-1, and vesicular stomatitis virus, but 5-cyano-2'-deoxyuridine, while lacking activity against herpes simplex, showed significant inhibition of vaccina virus; for instance, 5-cyano-2'-deoxyuridine inhibited vaccinia virus replication at concentrations 10-20 times that required for inhibition by the known antivirals, 5-iodo-2'-deoxyuridine and 1-(beta-D-arabinofuranosyl)adenine. Replacement of the 5-halogeno substituents of pyrimidine deoxyribonucleosides thus decreases, but does not abolish, antiviral activity.
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PMID:Improved synthesis and in vitro antiviral activities of 5-cyanouridine and 5-cyano-2'-deoxyuridine. 19 58

Of a series of 58 aliphatic nucleoside analogues, (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA] proved to be the most active congener, when assayed for antiviral activity in primary rabbit kidney cell cultures challenged with either vaccinia or vesicular stomatitis virus. Whereas most analogues derived from substituted purine and pyrimidine bases and bearing various hydroxy- or amino-substituted alkyl chains did not show evidence of antiviral activity at a concentration of 2 mM, (S)-DHPA inhibited both vaccinia and vesicular stomatitis virus replication at 0.05-0.1 mM. For 9-[(RS)-2,3-diazidopropyl]adenine and some di- and trihydroxybutyl analogues of DHPA, viz., 9-[(2RS,3SR)-2,3-dihydroxybutylladenine, 9-[(RS)- or 9-[(S)-3,4-dihydroxybutyl]adenine, 9-[(2S,3R)-2,3,4-trihydroxybutyl]adenine, and 3-(adenin-9-yl)-(RS)-alanine, an antiviral effect was noted at a concentration of 0.5-1 mM.
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PMID:Antiviral activity of aliphatic nucleoside analogues: structure-function relationship. 22 6

The denV gene from bacteriophage T4 encodes a pyrimidine dimer-specific endonuclease that has the capacity to initiate excision repair of DNA. Cells from excision repair-deficient xeroderma pigmentosum (XP) patients are able to carry out excision repair initiated by the denV gene product and introduction of the denV gene into XP cells results in the partial restoration of colony-forming ability after irradiation with UV light. In this work we have constructed a helper-independent recombinant human adenovirus, Ad5denV, which contains the denV gene. A 1.9 kb cartridge consisting of the denV gene flanked by the long terminal repeat (LTR) promoter from Rous sarcoma virus (RSV) and the simian virus 40 (SV40) polyadenylation (poly A) splice signals, was inserted into the E3 region of an E3 deletion mutant (Ad5d1E3) of adenovirus type 5. Infection of human fibroblasts and other permissive human cells with Ad5denV resulted in lytic infection and expression of the denV gene was confirmed by primer extension of infected cell RNA. The ability of the denV gene to restore the DNA repair deficiency in XP fibroblasts was examined using host cell reactivation of viral structural antigen formation for UV-irradiated adenovirus. The control virus, Ad5VSV, was also a recombinant which contained the gene for vesicular stomatitis virus glycoprotein G inserted into the E3 region of Ad5d1E3. UV survival of Ad5denV was similar to that of Ad5VSV following infection of two normal fibroblast strains and a Cockayne syndrome fibroblast strain, CS7SE, from complementation group B. In contrast, UV survival of Ad5denV was significantly greater than that for Ad5VSV after infection of three unrelated XP fibroblast strains from complementation groups A, C and E. However, UV survival of Ad5denV in the XP fibroblasts did not reach levels obtained in normal fibroblasts, indicating that restoration of the XP defect was partial.
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PMID:Construction of a recombinant adenovirus containing the denV gene from bacteriophage T4 which can partially restore the DNA repair deficiency in xeroderma pigmentosum fibroblasts. 170 21

Cyclopentenylcytosine (Ce-Cyd) is a broad-spectrum antiviral agent active against DNA viruses [herpes (cytomegalo), pox (vaccinia)], (+)RNA viruses [picorna (polio, Coxsackie, rhino), toga (Sindbis, Semliki forest), corona], (-)RNA viruses [orthomyxo (influenza), paramyxo (parainfluenza, measles), arena (Junin, Tacaribe), rhabdo (vesicular stomatitis)] and (+/-)RNA viruses (reo). Ce-Cyd is a more potent antiviral agent than its saturated counterpart, cyclopentylcytosine (carbodine, C-Cyd). Ce-Cyd also has potent cytocidal activity against a number of tumor cell lines. The putative target enzyme for both the antiviral and antitumor action of Ce-Cyd is assumed to be the CTP synthetase that converts UTP to CTP. In keeping with this hypothesis was the finding that the antiviral and cytocidal effects of Ce-Cyd are readily reversed by Cyd and, to a lesser extent, Urd, but not by other nucleosides such as dThd or dCyd. In contrast, pyrazofurin and 6-azauridine, two nucleoside analogues that are assumed to interfere with OMP decarboxylase, another enzyme involved in the biosynthesis of pyrimidine ribonucleotides, potentiate the cytocidal activity of Ce-Cyd. Ce-Cyd should be further pursued, as such and in combination with OMP decarboxylase inhibitors, for its therapeutic potential in the treatment of both viral and neoplastic diseases.
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PMID:Broad-spectrum antiviral and cytocidal activity of cyclopentenylcytosine, a carbocyclic nucleoside targeted at CTP synthetase. 171 Jan 19

The halogenated pyrimidine, iododeoxyuridine (IUdR), enhances cytotoxicity of ionizing irradiation experimentally. Continuous intraarterial infusion of IUdR was combined with irradiation to maximize drug concentration in tumor and reduce potential systemic toxicity. Percutaneous tumor-specific artery catheterization was utilized in five patients, with delivery of IUdR (20 mg/kg/day) by continuous infusion 5 days prior to irradiation treatments and continued for 10-14 days. Infusion vessels included the internal mammary, the internal iliac, the renal, the common femoral, and the bronchial arteries. Conventional radiotherapy fields, fractionation, and total doses were utilized, and therapy was well tolerated. Low-grade leukopenia and thrombocytopenia was observed several weeks following infusion. A clinically nonsignificant skin reaction was observed within the irradiation fields 2-3 weeks after initiation of irradiation in several patients. No alopecia or stomatitis was observed. This study minimizes initial hepatic dehalogenation of IUdR when given by intraarterial administration. Two patients have been free of disease for over 20 years, with no long-term toxicity from IUdR therapy.
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PMID:Intraarterial iododeoxyuridine infusion combined with irradiation. A pilot study. 237 11

Brequinar sodium (NSC 368390; DUP 785) is a new inhibitor of pyrimidine de novo biosynthesis which has completed Phase I clinical trials within the framework of the Early Clinical Trials Group of the European Organization for Research and Treatment of Cancer (EORTC). The main side effects of this compound are myelosuppression, nausea and vomiting, stomatitis and/or mucositis, and skin rash. In this report, the authors describe the pattern of mucocutaneous side effects of Brequinar sodium in patients who received the drug by four different schedules: (1) short-term intravenous (IV) infusion every 3 weeks; (2) weekly; (3) twice weekly; and (4) five times daily every 4 weeks. Mucocutaneous toxicities of Brequinar sodium included mainly cytotoxic reactions (stomatitis and/or mucositis and skin rash). However, rare episodes of local reactions (phlebitis at the site of injection), photosensitivity reactions (to sun light), angioneurotic edema, and localized secondary hyperpigmentation of the inflamed skin also occurred. Stomatitis and/or mucositis appeared to be dose-dependent and schedule-dependent. The skin rash consisted of a drug-induced toxic dermatitis which occurred mostly at the highest dose levels. Initial recommendations for the management of mucocutaneous toxicities of Brequinar sodium during Phase II trials are discussed.
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PMID:Mucocutaneous side effects of Brequinar sodium. A new inhibitor of pyrimidine de novo biosynthesis. 252 Dec 97

Brequinar, DUP 785, is a substituted 4-quinoline carboxylic acid derivative which in preclinical studies has shown broad antitumor activity. It is a novel antimetabolite blocking pyrimidine nucleotide synthesis. In a clinical phase I study, 83 patients were treated on a weekly schedule and 18 patients on a biweekly schedule. The drug was given intravenously as a short infusion. Three patients were entered on each dose level from a starting dose of 6 mg/m2 up to 2600 mg/m2 weekly. The dose ranges on a biweekly schedule were 500-850 mg/m2. There was no dose escalation in individual patients. Pharmacokinetic studies were performed in 19 patients on a weekly schedule and in two patients on a biweekly schedule. A biphasic decay in plasma was observed with a median half life of 10 h (5.1-23.4). The main dose-limiting toxicity was thrombocytopenia. Of non-hematologic side-effects, stomatitis/mucositis occurred frequently. Skin eruptions occurred rarely, but were a major problem when found. All side-effects were fully reversible; there were no signs of cumulative toxicity. Antitumor activity was observed in one patient with a lung metastasis from a bladder cancer and in a patient with an unknown primary tumor. The recommended doses for phase II trials with DUP 785 are: 1500-2000 mg/m2 on a weekly schedule and 500-750 mg/m2 on a biweekly schedule dependent on status before treatment.
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PMID:A phase I clinical and pharmacokinetic study of Brequinar sodium, DUP 785 (NSC 368390), using a weekly and a biweekly schedule. 259 33

A novel immunopotentiating agent, 5-amino-3-beta-D-ribofuranosylthiazolo [4,5-d]pyrimidine-2,7(3H,6H)-dione (7-thia-8-oxoguanosine), lacks virus-inhibitory properties in vitro but induces interferon and potentiates immune functions, such as natural killer cell activity. It was evaluated in rodent models to determine the spectrum of antiviral activity and effective treatment regimens. At 50 to 200 mg/kg given as single or divided intraperitoneal (i.p.) doses 1 day before virus inoculation, significant protection was afforded to mice infected i.p. with Semliki Forest, San Angelo, banzi, and encephalomyocarditis viruses. Similarly, suckling rats were protected from an intranasal challenge with rat coronavirus. Against San Angelo virus, treatments could be delayed to 1 day post-virus inoculation and still show a beneficial effect. The compound was moderately effective in mice infected i.p. with herpes simplex virus type 2 or intranasally with vesicular stomatitis virus. No activity was seen against influenza B virus in mice when the analog was administered one time pre-virus inoculation or in multiple doses given before and after the virus inoculation. Nor was there a prophylactic effect against herpetic skin lesions on mice. This immune modulator may have promise for the treatment of a variety of virus infections.
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PMID:Broad-spectrum in vivo antiviral activity of 7-thia-8-oxoguanosine, a novel immunopotentiating agent. 281 49

The purified RNA polymerase complex of vesicular stomatitis virus required added thiols for maximal activity, whereas polymerase activity from whole disrupted virions did not. Maximal activity of the purified polymerase complex required greater than or equal to 1 mM added dithiothreitol. The polymerase was inactivated by N-ethylmaleimide (NEM) at 0 degree C, with k2 = 528 +/- 26 M-1 min-1. Activity was recovered by addition of L protein, but not N or NS, to the NEM-inactivated complex, indicating that the NEM-sensitive group was present on the L protein. Nucleoside triphosphates protected the enzyme against inactivation by N-ethylmaleimide. ATP was most effective, with KD = 0.58 +/- 0.07 mM, a value close to the Km of ATP reported previously for initiation of RNA synthesis. dATP was nearly as effective, and GTP was slightly less effective than ATP. Non-hydrolyzable analogs of ATP protected weakly, whereas ADP and pyrimidine triphosphates gave very poor, but still measurable, protection. The ATP binding site thus identified differs from the protein kinase-associated ATP binding site identified on L protein by Sanchez et al. (Sanchez, A., De, B.P., and Banerjee, A. K. (1985) J. Gen. Virol. 66, 1025-1036) in having a substantially lower affinity for ATP. Two putative ATP binding sites were identified in the L protein amino acid sequence, but none were found in the N or NS sequences.
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PMID:Inactivation of the RNA polymerase of vesicular stomatitis virus by N-ethylmaleimide and protection by nucleoside triphosphates. Evidence for a second ATP binding site on L protein. 303 24


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