Cellular DNA synthesis

Idoxuridine (Herplex) is a water-soluble iodinated derivative of deoxyuridine that inhibits several DNA viruses including HSV, VZV, vaccinia, and polyoma virus. The triphosphorylated metabolite of idoxuridine inhibits both viral and cellular DNA synthesis and is also incorporated into DNA. Such modified DNA is susceptible to strand breakage and causes aberrant viral protein synthesis. Because of its significant host cytotoxicity, idoxuridine cannot be used to treat systemic viral infections The development of resistance to this drug is common. 

Cidofovir (Figure 24.4) is an antiviral cytidine nucleotide analog with inhibitory activity against HCMV and other herpes viruses. Cidofovir is first converted to an active diphosphate form by cellular enzymes. Antiviral effects of cidofovir are due to inhibition of viral DNA polymerase by the diphosphate metabolite (Neyts and De Clercq, 1994 Plosker and Noble, 1999 Scholar and Pratt, 2000). The diphosphate probably interacts with DNA polymerase either as an alternate substrate (incorporation at the 3 end or within the interior of the DNA chain) or as a competitive inhibitor (with respect to the normal substrate dCTP). Cidofovir inhibits HCMV DNA synthesis at intracellular concentrations 1000-fold lower than are required to inhibit cellular DNA synthesis (Neyts and De Clercq, 1994). For HSV-1 and HSV-2 corresponding concentrations are at least 50-fold lower. 

A causal relationship between lithium treatment and hyperparathyroidism has been suggested [37]. Lithium seems to induce morphological changes in the parathyroid glands with an increase in parathyroid volume, and an increase in cellular DNA synthesis [37-39], which may explain why its effects may not be completely reversible. It is not rare to find patients with hypercalcemia, usually mild, after discontinuation of prolonged lithium therapy. A number of cases have been reported where hypercalcemia and hypocalciuria persisted even after discontinuation. We also have seen persistence of hypercalcemia and hyperparathyroidism several years after discontinuation of lithium therapy [Batlle et al unpublished, 2000]. 

Trifluridine inhibits replication of herpesviruses, including acyclovir-resistant strains. Trifluridine also inhibits cellular DNA synthesis at relatively low concentrations. 

The phosphonate acyclic nucleosides, 174-177 (Fig. 30), are broad spectrum antiviral agents active against DNA and retroviruses [207]. They are a family of structurally related compounds of which 175-177 show significant anti-HIV activity [208]. The mechanism of action of 175-177 remains to be elucidated. For the structurally related 174, it has been shown that it can, as such, be incorporated by the cells. Then, it is converted to the mono and diphosphoryl derivatives by cellular enzymes. The latter diphosphorylphosphonate, which can be considered as an analog of nucleoside-5 -triphosphate, may be the active form of the molecule, which inhibits viral DNA synthesis at concentrations which are by several orders of magnitude lower than those required for inhibition of cellular DNA synthesis. Similarly the anti-HIV activity of 175 may be attributed to a specific inhibition of the viral RNA-directed DNA synthesis. 

The results of the Ames test for mutagenesis Indicate that many ruthenium compounds Introduce serious lesions into cellular genetic material so that an error-prone DNA repair mechanism is Induced. These results are similar to those obtained for clsplatln (M) and suggest that these complexes probably bind directly to nuclear DNA. In concert with this, many of the ruthenium complexes also Inhibit cellular DNA synthesis (H, ), another property also noted for the cls-platlnum drugs. Unfortunately, however, there Is no correlation between either of these studies and the antitumor activity of ruthenium compounds tested In animal systems. 

Cycloaddition reactions play the most important role in tetrazine chemistry. Lately, this has been widely explored in bio-orthogonal chemistry where tetrazine acts as the reactive group of different reporters in conjugation with a reactive tag of a biomolecule. For example, 5-vinyl-2 -deoxyuridine 46 was reported to be a metabolic probe for cellular DNA synthesis that can be visualized by using an... 

Thymidylate residues required for cellular DNA synthesis are obtained exogenously via the salvage pathway and/or are synthesised de novo via dUMP in a reaction catalysed by thymidylate synthase (dUMP dXMP). The thymidine monophosphate can then be phosphorylated by kinases to dTDP and dTTP before being incorporated into DNA. 

The inhibition of cellular DNA synthesis by picomaviruses is expressed later in infection than the depression of cellular protein or ENA synthesis. In mengovirus infected L-cells (I7, 23) the inhibition starts within 2 hoxirs and is virtually completed by 6 hours. Between 2 and 5 hours after infection, the primary DNA synthetic event blocked by mengovirus is the multifocal initiation of new DNA chain synthesis (23). However, by 6 hours, replication fork movement is also retarded and there is a more generalized derangement in DNA synthesis (24). 

This manuscript describes two murine T-cell lymphoma clones, MYCO-IA and MYCO-lA-20, with genetically altered IMP dehydrogenase activities. These clones were isolated by virtue of their resistance to mycophenolic acid, a potent inhibitor of cellular DNA synthesis (9) and of both IMP dehydrogenase and GMP synthetase enzyme activities (10). The MYCO-lA and MYCO-lA-20 clones were isolated from semi-solid agarose containing 1 uM and 20 vM mycophenolic acid, respectively. In comparative growth rate experiments, the MYCO-IA and MYCO-lA-20 cell lines were 3- and 50-fold less sensitive than wild-type cells to the growth... 

Considering the central role of folic acid in cellular DNA synthesis it would not be surprising that the immune response, which requires rapid proliferation of sensitized cells would be affected by a deficiency of this cofactor. However, there have been few systematic studies of the effect of folate deficiency on immunocompetence in either animal or human models. Table I summarizes the alterations in humoral and cell-mediated immunity which have been observed in patients with megaloblastic anemia due to folate deficiency as well as studies in folate deficient animals. 

Ben-Porat, T., and Kaplan, A. S., 1965, Mechanism of inhibition of cellular DNA synthesis by pseudorabies virus. Virology 25 22. 

Ludwig, H., and Rott, R., 1975, Effect of 2-deoxyglucose on herpes virus-induced inhibition of cellular DNA synthesis, J. Virol. 16 217. 

Shaw, J. E., and Cox, D. C., 1973, Early inhibition of cellular DNA synthesis by high multiplicities of infectious and UV-inactivated reovirus, J. Virol. 12 704. 

Simizu, B., Wagatsuma, B., Oya, M., Hanaoka, F., and Yamada, M., 1976, Inhibition of cellular DNA synthesis in hamster kidney cells infected with western equine encephalitis virus, Arch. Virol. 51 251. 

Effect of VSV on Cellular and Viral DNA Synthesis 5.7.1. Parameters of Cellular DNA Synthesis Inhibition... 

Viral Functions Required to Inhibit Cellular DNA Synthesis... 

The effect of VSV on cellular DNA synthesis could result from perturbation of cellular structures similar to those conceivably involved in inhibition of RNA and protein synthesis. The effect is unlikely to be at the limiting cell membrane because McGowan and Wagner (1981) found that VSV infection does not significantly alter uptake of thymidine into soluble intracellular pools of nucleosides. 

Much more research is required for definitive identification of the leader RNA sequences which inhibit RNA synthesis and particularly those that inhibit cellular DNA synthesis. Little is known about the cellular targets for virus inhibition of RNA and DNA synthesis. 

Inhibition of Cellular DNA Synthesis in Productively-Infected Cells... 

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