Induction of Both Thymidine and Deoxycytidine Kinase Activity by Herpes Viruses

The pathogenicity of thymidine kinase-deficient mutants of herpes simplex virus in mice

“…Serum-starved BHK cells Stationary cultures of BHK cells were obtained using the method of serumstarvation described by Jamieson et al (1974). Dishes were seeded with 106 cells in normal medium.…”

“…For example, herpes simplex virus is known to induce virus-specific thymidine kinase (TK) activity, and this is associated with a serologically virus-specific protein (Klemperer et al 1967, Thouless & Wildy, 1975. However, virus mutants (TK-) deficient inthe production of this enzyme have been found which replicate efficiently in standard cell cultures, though not in serum-starved cells (Jamieson, Gentry & Subak-Sharpe, 1974). It has been suggested that cells infected in the natural disease such as epidermal and neural cells may have low levels of thymidilate metabolism and in these cells the virus may benefit from this apparently unnecessary enzyme.…”

History of Oncolytic Viruses: Genesis to Genetic Engineering

“…Although a mutant HSV lacking the enzymatic activity of thymidine kinase had been isolated almost twenty years previously, 86 not until Martuza et al's work was its potential as a cancer therapeutic appreciated. By extending on the observation that a thymidine kinase-negative HSV replicated in dividing cells but was crippled in non-dividing cells, Martuza was able to apply HSV-thymidine kinase to treat malignant gliomas by intra-cerebral inoculation in mice, thereby eradicating tumors completely.…”

Antiviral Activity of Arabinosylthymine in Herpesviral Replication: Mechanism of Action In Vivo and In Vitro

“…Subsequently, ara-T was found to have little effect on the multiplication of tumor cells in culture (11,15) but was later shown to be somewhat inhibitory to herpesvirus replication in vivo (17,18,53,54,56). The demonstration (26) that herpes simplex virus (HSV)-infected cells contain a pyrimidine deoxyribonucleoside kinase (dPyK) with a broad substrate specificity (29,30) suggested that ara-T might be phospho- ' rylated in HSV-infected cell cultures, but not in uninfected ones, and might therefore show a selectivity that, at that time (1974), was not ordinarily associated with inhibitors of virus replication. A reinvestigation supported this suggestion by showing that ara-T at 2 x 10-M completely blocked the replication of HSV type 1 (HSV-1) and HSV type 2 (HSV-2) in BHK cells but had no measurable effect on the multiplication of uninfected BHK cells subcultured at low cell density and followed for several generations (23).…”

“…Subsequently, ara-T was found to have little effect on the multiplication of tumor cells in culture (11,15) but was later shown to be somewhat inhibitory to herpesvirus replication in vivo (17,18,53,54,56). The demonstration (26) that herpes simplex virus (HSV)-infected cells contain a pyrimidine deoxyribonucleoside kinase (dPyK) with a broad substrate specificity (29,30) suggested that ara-T might be phospho- showing that ara-T at 2 x 10-M completely blocked the replication of HSV type 1 (HSV-1) and HSV type 2 (HSV-2) in BHK cells but had no measurable effect on the multiplication of uninfected BHK cells subcultured at low cell density and followed for several generations (23). It has subsequently been shown that several other deoythymidine (dT) analogs have similar selectivity against HSV, including 5'-amino-2',5'-dideoxy-5-iodouridine, 5-ethyldeoxyuridine, 5-propyldeoxyuridine, 5-allyldeoxyuridine (8, 10); 5-bromodeoxycytidine, 5-iododeoxycytidine (13,20, 24,31); and 5-methoxymethyldeoxyuridine (2,3).…”