193 research outputs found
THE SELECTIVE INHIBITION OF VIRAL DNA SYNTHESIS BY CHEMOTHERAPEUTIC AGENTS: AN INDICATOR OF CLINICAL USEFULNESS? *
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72533/1/j.1749-6632.1977.tb21976.x.pd
Antiviral activity of 2,3-Dihydro-1H-imidazo[1,2-b]pyrazole in herpes simplex virus type 1-infected mammalian cells
2,3-Dihydro-1H-imidazo[1,2-b]pyrazole (IMPY), a known inhibitor of DNA synthesis, has been shown to be a useful drug for the synchronization of mammalian cells in culture. Recent studies in our laboratory indicate that IMPY may possess significant antiviral activity against herpes simplex virus (HSV) type 1. IMPY. at a concentration of 80 [mu]g/ml or 0.73 mM, reduced syncytia formation approximately 80 per cent. A 50 per cent inhibitory dose was calculated for each drug in order to compare potency in syncytia reduction of IMPY with that of arabinosyladenine (ara-A) and arabinosyl-hypoxanthine (ara-H). Our results indicated that the antiviral potencies of the three drugs were ranked in the order ara-A > ara-H > IMPY, the 50 per cent inhibitory doses being 22, 195 and 309 [mu]M respectively. Utilizing the microplate procedure of Sidwell and Huffman [Appl. Microbiol. 22, 797 (1971)], inhibition of viral cytopathic effect was rated against drug cytotoxicity and a virus rating (VR) established. A virus rating of 0.68 was calculated for IMPY. In comparison, VR values of 0.84 and 0.66 were obtained for ara-A and ara-H respectively. In contrast to the syncytia reduction studies, IMPY appeared to possess antiviral activity equivalent to that of ara-H according to the criteria of the virus rating assay. A technique was developed for evaluating the degree of selectivity ([deg]S) of a drug with respect to its differential effect on viral and cellular DNA synthesis. IMPY was found to possess a negative selectivity at all concentrations studied, reflecting the fact that it inhibited cellular DNA synthesis more than viral DNA synthesis. In contrast, ara-A and ara-H both expressed positive degrees of selectivity in that they inhibited viral DNA synthesis more extensively than cellular DNA synthesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21651/1/0000035.pd
Selective inhibition of herpes simplex virus ribonucleoside diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone
The effects of thiosemicarbazone derivatives of 2-acetylpyridine on mammalian and viral ribonucleoside diphosphate reductases were investigated. The enzymes were partially purified from uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells by sequential salt fractionation with streptomycin sulfate and ammonium sulfate and by affinity chromatography on ATP-agarose. The five thiosemicarbazone derivatives investigated were all potent inhibitors of the virus-induced reductase. Fifty percent inhibitory concentrations (50 values) range from 2 to 13 [mu]M. Four of the five derivatives also were inhibitors of the host cell reductase . A semicarbazone was inactive against the cellular enzyme and relatively weak as an inhibitor of the viral enzyme . Four of the six compounds were preferential inhibitors of the viral reductase based on a comparison of 50 values (5- to > 85-fold difference). Kinetic experiments revealed that inhibition of the HSV-1 reductase by the thiosemicarbazones was noncompetitive with respect to CDP and dithiothreitol. A comparison of the inhibitory effects of 2-acetylpyridine thiosemicarbazone itself on viral reductase and on virus replication in vitro demonstrated a similarity in the dose-response relationships for the two parameters. This observation supports the hypothesis that the HSV-induced ribonucleoside diphosphate reductase is an important target for the design of antiviral drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26189/1/0000268.pd
Prevalence of type R virus-like particles in clones of BHK-21 cells
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32926/1/0000308.pd
Systems approach to the study of drug transport across membranes using suspension cultures of mammalian cells V. Simultaneous passive transport and biosynthesis
A physical model is described for the simultaneous enzymatic bioconversion of a nonelectrolyte solute and the passive transport of both the solute and product of the enzymatic reaction out of cells in culture suspension. The plasma membrane is assumed to be the rate-determining transport barrier. This model provides the basis for the experimental design and analysis of the Michaelis-Menten kinetic parameters of simple enzymatic reactions in situ, the phenomenological transport parameters and other factors. The primary set of differential equations describing the quasisteady state rate of change in the concentration of the solute and product within the cell due to enzyme reaction and transport are given. These are nonlinear and must be solved by numerical methods. However, analytical mathematical expressions have been derived for various cases in the limit when the rate of enzymatic reaction is first or zero order.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21657/1/0000041.pd
A microtiter virus yield reduction assay for the evaluation of antiviral compounds against human cytomegalovirus and herpes simplex virus
Although the virus yield reduction assay is a powerful technique for evaluating the efficacy of antiviral compounds, it is not routinely utilized due to its labor-intensive nature. This procedure was modified, developed, thereby reducing greatly the time and effort required to perform yield reduction assays. Monolayer cultures of mammalian cells were grown in 96-well microtiter tissue culture plates and infected with virus. Test compounds were added and serially diluted directly with the plates. Following a cycle of virus replication, culture lysates were made and serially diluted in a separate set of uninfected cultures grown in microtiter plates. The cultures were incubated, plaques were enumerated in wells containing 5 to 20 plaques, and virus titers were calculated. To illustrate the use of the assay the known antiviral drugs acyclovir and ganciclovir were evaluated using this procedure. Ninety percent inhibitory concentrations for the respective drugs were 3 [mu]M and 0.7 [mu]M against herpes simplex virus type 1 and 60 [mu]M and 1 [mu]M against human cytomegalovirus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28636/1/0000450.pd
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Atmospheric sampling of Supertyphoon Mireille with NASA DC-8 aircraft on September 27,1991, during PEM-West A
The DC-8 mission of September 27, 1991, was designed to sample air flowing into Typhoon Mireille in the boundary layer, air in the upper tropospheric eye region, and air emerging from the typhoon and ahead of the system, also in the upper troposphere. The objective was to find how a typhoon redistributes trace constituents in the West Pacific region and whether any such redistribution is important on the global scale. The boundary layer air (300 m), in a region to the SE of the eye, contained low mixing ratios of the tracer species O3, CO, C2H6, C2H2, C3H8, C6H6and CS2 but high values of dimethylsulfide (DMS). The eye region relative to the boundary layer, showed somewhat elevated levels of CO, substantially increased levels of O3, CS2 and all nonmethane hydrocarbons (NMHCs), and somewhat reduced levels of DMS. Ahead of the eye, CO and the NMHCs remained unchanged, O3 and CS2 showed a modest decrease, and DMS showed a substantial decrease. There was no evidence from lidar cross sections of ozone for the downward entrainment of stratospheric air into the eye region; these sections show that low ozone values were measured in the troposphere. The DMS data suggest substantial entrainment of boundary layer air into the system, particularly into the eye wall region. Estimates of the DMS sulphur flux between the boundary layer and the free troposphere, based on computations of velocity potential and divergent winds, gave values of about 69 ΞΌg S mβ2 dβ1 averaged over a 17.5Β° grid square encompassing the typhoon. A few hours after sampling with the DC-8, Mireille passed over Oki Island, just to the north of Japan, producing surface values of ozone of 5.5 ppbv. These O3 levels are consistent with the low tropospheric values found by lidar and are more typical of equatorial regions. We suggest that the central eye region may act like a Taylor column which has moved poleward from low latitudes. The high-altitude photochemical environment within Typhoon Mireille was found to be quite active as evidenced by significant levels of measured gas phase H2O2 and CH3OOH and model-computed levels of OH
Bisphosphonates as antimyeloma drugs
In patients with symptomatic multiple myeloma (MM), bisphosphonate (BP) treatment has been widely used to prevent bone loss and preserve skeletal health because of its proven effects on inhibiting osteoclast-mediated bone resorption. In addition to their effects on osteoclasts, it is becoming increasingly evident that BPs may have additional effects on the bone microenvironment and cells other than osteoclasts that may potentially inhibit the development and progression of MM. This review focuses on the pathophysiology of MM with an emphasis on the events that drive MM progression within the bone and the mechanisms by which BPs may inhibit specific processes. The underlying molecular mechanisms that drive the modulation of cellular fate and function and consequent physiological outcomes are described. Direct effects on myeloma cell growth and survival and the interactions between myeloma cells and the bone microenvironment are discussed. Clinical evidence of the antimyeloma effects of BPs is emerging and is also reviewed
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