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The inhibitory effects of two anionic compounds, Evans blue and aurintricarboxylic acid (ATA), on various kinds of polynucleotide-synthesizing enzymes were examined. Under the assay conditions, optimized for each enzyme species, both these compounds strongly inhibited the activities of the purified human DNA polymerases alpha, beta, gamma, and DNA primase as well as those of DNA polymerase I and RNA polymerase from Escherichia coli and Rauscher leukemia virus reverse transcriptase. ATA was particularly effective in inhibiting retroviral reverse transcriptase and cellular DNA polymerase alpha. Evans blue, which is a structural analogue of suramin, exerted its inhibitory action largely by competing with the template.primer for the same binding site of the enzyme. On the other hand, ATA inhibited most, if not all, of these enzyme activities noncompetitively with respect to either the template.primers or nucleoside 5'-triphosphate substrates. The inhibition constants for ATA were, in general, smaller than those for Evans blue.
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(E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU, Brivudin, Zostex®, Zerpex®, Zonavir®), now more than 20 years after its discovery, still stands out as a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. It has been used in the topical treatment of herpetic keratitis and recurrent herpes labialis and the systemic (oral) treatment of herpes zoster (zona, shingles). The high selectivity of BVDU towards HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5′-diphosphate (DP) by the virus-encoded thymidine kinase (TK). After further phosphorylation (by cellular enzymes), to the 5′-triphosphate (TP), the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. This finding offers considerable potential in a combined gene therapy/chemotherapy approach for cancer. To the extent that BVDU or its analogues (i.e., BVaraU) are degraded (by thymidine phosphorylase) to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. The prime determinant in the unique behavior of BVDU is its (E)-5-(2-bromovinyl) substituent. Numerous BVDU analogues have been described that, when equipped with this particular pharmacophore, demonstrate an activity spectrum characteristic of BVDU, including selective anti-VZV activity. © 2004 Wiley Periodicals, Inc.
Selective laser sintering (SLS) is one of the most rapidly growing rapid prototyping techniques (RPT). This is mainly due to its suitability to process almost any material: polymers, metals, ceramics (including foundry sand) and many types of composites. The material should be supplied as powder that may occasionally contain a sacrificial polymer binder that has to be removed (debinded) afterwards. The interaction between the laser beam and the powder material used in SLS is one of the dominant phenomena that defines the feasibility and quality of any SLS process. This paper surveys the current state of SLS in terms of materials and lasers. It describes investigations carried out experimentally and by numerical simulation in order to get insight into laser‐material interaction and to control this interaction properly.
Human papilloma virus (HPV)-associated diseases are increasingly diagnosed in solid organ recipients. Cidofovir (CDV) is a broad-spectrum antiviral agent with activity against all human herpes viruses and HPV. From 2000-2004, a total of 1303 solid organ transplants (SOT) were performed at our center. Six transplant recipients were treated with topical CDV for HPV-associated lesions. One cardiac recipient responded to a single injection of CDV into his recurrent anal condylomata. In a renal recipient with recurrent penile condylomata CDV was injected into the lesions four times (2 week interval) until lesions regressed. One renal recipient developed multiple vaginal and anal intradermal neoplasias, which relapsed after laser ablation. The lesions were repeatedly injected with CDV and completely disappeared. Two renal recipients with widespread verrucae vulgares were treated with CDV gel, which resulted in regression of the lesions. One patient developed donor derived verrucae vulgares on both transplanted hands, which responded to CDV gel. Four of the six patients were switched from calcineurin inhibitors (CNIs) to Sirolimus (SIR). CDV was found effective in the treatment of HPV-associated skin lesions in SOT recipients. It needs to be determined whether switch from CNIs to SIR might have contributed to the beneficial effect of CDV.
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