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, more or fewer than the usual diploid number of chromosomes) The characteristics usually involved in these assays are resistance to 8-azaguanine or 6-thioguanine (the hypoxanthine guanine phosphoribosyl transferase or HGPRT locus), resistance to bromodeoxyuridine or tri urothymidine (the thymidine kinase or TK locus), or resistance to ouabain (the OU or Na/K-ATPase locus) HGPRT is responsible for incorporation of purines from the medium into the nucleic acid synthesis pathway Its loss prevents uptake of normal purines and also of toxic purines such as 8-azaguanine, which would kill the cell Thus mutation at this locus confers resistance to these toxic purine analogues Similarly TK permits pyrimidine transport, and its loss prevents uptake of toxic pyrimidine analogues and confers resistance to them In the absence of HGPRT or TK, the cells can grow by de novo synthesis of purines and pyrimidines Ouabain kills cells by combining with the Na/K-ATPase.

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Mutation at the OU locus alters the ouabain-binding site in a way that prevents inhibition and thus confers resistance A typical test system is the analysis of the TK locus in mouse lymphoma cells for mutations that confer resistance to bromodeoxyuracil The tests are conducted with and without the S-9 fraction from induced rat liver because the lymphoma cells have little activating ability Both positive and negative controls are included, and the parameter.

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; Sidwell, R W Vaccinia skin lesions in immunosuppressed hairless mice can be treated topically but not parenterally with cidofovir Antiviral Res 2003, 57, A79 164 Huggins, J W; Smee, D F; Martinez, M J; Bray, M Cidofovir (HPMPC) treatment of monkeypox Antiviral Res 1998, 37, A73 165 Beadle, J R; Valiaeva, N; Brad Wan, W; Hostetler, K Y Direct synthesis of acyclic nucleoside phosphonate alkoxyalkyl monoesters Antiviral Res 2004, 62, A66 A67 166 Keith, K A; Wan, W B; Ciesla, S L; Beadle, J R; Hostetler, K Y; Kern, E R Inhibitory activity of alkoxyalkyl and alkyl esters of cidofovir and cyclic cidofovir against orthopoxvirus replication in vitro Antimicrob Agents Chemother 2004, 48, 1869 1871..

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measured is the number of cells formed that are capable of forming colonies in the presence of bromodeoxyuridine.

Let the bandwidths be b1 100 and b2 0. Since m G1 2:89 and m G2 1:00, the steady-state mean is EB I 100m G1 74:29: m G1 m G2

167 Huggins, J W; Baker, R O; Beadle, J R; Hostetler, K Y Orally active ether lipid prodrugs of cidofovir for the treatment of smallpox Antiviral Res 2002, 53, A66 168 Aldern, K A; Ciesla, S L; Winegarden, K L; Hostetler, K Y Increased antiviral activity of 1-O-hexadecyloxypropyl-[2-14C]cidofovir in MRC-5 human lung broblasts is explained by unique cellular uptake and metabolism Mol Pharmacol 2003, 63, 678 681 169 Ciesla, S L; Trahan, J; Wan, W B; Beadle, J R; Aldern, K A; Painter, G R; Hostetler, K Y Esteri cation of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney Antiviral Res 2003, 59, 163 171 170 Quenelle, D C; Collins, D J; Wan, W B; Beadle, J R; Hostetler, K Y; Kern, E R.

Let the initial level be 1. Since G1 has an exponential component with mean 100, we anticipate the time to reach the steady state to be between 100 and 1000. In Fig. 17.1 we plot the conditional mean m1 tjx for x 0:5, 5.0, and 50.0, computed by

Drosophila Sex-Linked Recessive Lethal Test The advantages of Drosophila (fruit y) tests are that they involve an intact eukaryotic organism with all of its interrelated organ systems and activation mechanisms but, at the same time, are fast, relatively easy to perform, and do not involve mammals as test animals The most obvious disadvantages are that the hormonal and immune systems of insects are signi cantly different from those of mammals and that the nature, speci city, and inducibility of the cytochrome P450s are not as well understood in insects as they are in mammals In a typical test, males that are 2 days postpuparium and that were raised from eggs laid within a short time period (usually 24 hours) are treated with the test compound in water to which sucrose has been added to increase palatability.

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Males from a strain carrying a gene for yellow body on the X chromosome are used Preliminary tests determine that the number of offspring of the survivors of the treatment doses (usually 025 LD50 and 05 LD50) are adequate for future crosses Appropriate controls, including a solvent control (with emulsi er if one was necessary to prepare the test solution), and a positive control, such as ethyl methane sulfonate, are routinely included with each test Individual crosses of each surviving treated male with a series of three females are made on a 0- to 2-, 3- to 5-, and 6- to 8-day schedule The progeny of each female is reared separately, and the males and females of the F1 generation are mated in brother-sister matings.

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