The release of previously cleared interferon by cycloheximide was studied in the mouse. When cycloheximide was administered after either endogenous interferon stimulation or administration of exogenous interferon, the clearance of interferon from the blood stream was interrupted and a sharp rise in interferon titer occurred approximately 6 hr after cycloheximide administration followed by a rapid decline to low levels. This effect was observed with either interferon stimulated endogenously (by polyriboinosinic.polyribocytidylic acid), or homologous (mouse) or heterologous (rabbit) interferon administered exogenously. Serum protein concentrations also exhibited this rise and fall phenomenon after cycloheximide administration although the magnitude of the change in protein concentrations was less pronounced than that observed with interferon. Hematocrits, although elevated in mice receiving cycloheximide, did not exhibit this rise and fall phenomenon. Hence, cycloheximide administration leads to the release into the circulation of previously cleared interferon as well as other proteins.
No abstract is provided for this article.
The Index introduces interesting new perspectives. Following its implementation in the Belgian pilot site in the CORINES project, further studies remain to be carried out in order to develop a cost/benefit assessment.
(E)-5-(2-Bromovinyl)-2'-deoxyuridine 5'-triphosphate (BrVdUTP) and (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil 5'-triphosphate (BrVarafUTP), which are known as specific inhibitors of herpes simplex viral (type 1 and 2) DNA polymerase, were found to be strong inhibitors of DNA polymerase gamma from human KB and murine myeloma cells. In fact BrVdUTP and BrVarafUTP were found to be stronger inhibitors of DNA polymerase gamma than of other DNA polymerases having viral (herpes simplex virus or retrovirus) origin or cellular (eukaryotic alpha and beta, or prokaryotic) origin. The mode of inhibition of DNA polymerase gamma by BrVdUTP and BrVarafUTP was competitive with respect to dTTP, the normal substrate. Whereas BrVdUTP was an efficient substrate for DNA polymerase gamma and other DNA polymerases that were examined, BrVarafUTP failed to serve as a substrate for DNA synthesis. Ki values for BrVdUTP (40 nM) and BrVarafUTP (7 nM) with DNA polymerase gamma, as determined with (rA)n.(dT) as the template.primer, were much smaller than the Km values for dTTP (0.16 microM and 0.71 microM for murine and human DNA polymerase gamma, respectively). Thus, the affinity of BrVdUTP or BrVarafUTP for DNA polymerase gamma was much stronger than that of dTTP.
This review article will describe the (wide) variety of approaches that I envisaged to develop a specific therapy for viral infections: (i) interferon and its inducers, (ii) HSV, VZV and CMV inhibitors, (iii) NRTIs (nucleoside reverse transcriptase inhibitors), NtRTIs (nucleotide reverse transcriptase inhibitors) and NNRTIs (non-nucleoside reverse transcriptase inhibitors) as HIV inhibitors, (iv) NtRTIs as HBV inhibitors, and finally, (v) the transition of an HIV inhibitor to a stem cell mobilizer, as exemplified by AMD-3100 (Mozobil<sup>®</sup>).
