5-Ethyl-2?-deoxyuridine: Absence of effects on the chromosomes of human lymphocytes and fibroblasts in culture

Singh, Surjit; Willers, I.; Goedde, H. W.; Gauri, K. K.

doi:10.1007/bf00283770

Cited by 12 publications

(8 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This communication reports the results of a comparative study on the antiviral and cytotoxic effects of all four analogues and suggests that selective affinity to various TK's is responsible for their differential activity. Some studies on the biological activity of 5ethyl-, 5-vinyl-, and 5-allyl-dUrd have been reported previously by other investigators (2,7,(9)(10)(11).…”

mentioning

confidence: 75%

Antiviral Action and Cellular Toxicity of Four Thymidine Analogues: 5-Ethyl-, 5-Vinyl-, 5-Propyl-, and 5-Allyl-2′-Deoxyuridine

Cheng

Domin

Sharma

et al. 1976

Antimicrob Agents Chemother

106

View full text Add to dashboard Cite

5-Ethyl-, 5-vinyl-, 5-propyl-, and 5-allyl-2'-deoxyuridine (dUrd) had antiviral activity against herpes simplex type 1 and type 2 grown in HeLa TK-cells, in the order 5-vinyl-dUrd, 5-ethyl-dUrd, 5-propyl-dUrd, 5-allyl-dUrd, but they were inactive against a TK-mutant of herpes simplex type 1. The antiviral activity of these compounds could be partially reversed by thymidine. Except for 5-vinyl-dUrd, they were not toxic to WI-38 and HeLa TK-cells at a concentration of 25 ,uM. All four analogues inhibited the growth of herpes simplex type 1-transformed HeLa TK-cells at a concentration of 1 ,uM.Herpesviruses are responsible for many diseases in man, and recent evidence also suggests a strong correlation between herpes infections and the incidence of certain human malignancies (4). One characteristic of herpes simplex type I (HSV-1) and type II (HSV-2) is that they can induce virus-specific thymidine kinases (TK) in some human cells after infection. These viral TK's are different from the cytoplasmic and mitochondrial TK's of human cells not only with respect to their physical and chemical properties, such as electrophoretic mobility, activation energy, and salt sensitivity, but also in substrate specificity (Y. C. Cheng, submitted for publication; L. S. Lee and Y. C. Cheng, submitted for publication). This fact suggested to us that specific anti-HSV-1 and HSV-2 agents that specifically utilize viral TK might be developed.The approach taken in this laboratory is to seek analogues of thymidine that could act as alternative substrates for viral TK Chem., in press). A previous study on the binding specificity of some pyrimidine 2'-deoxyribonucleosides showed that 5-ethyl-, 5-propyl-, and 5-allyl-deoxyuridine (dUrd) had good binding affinity to HSV-1-and HSV-2-specific TK's (Km of thymidine to Ki of analogue less than 0.2) but much poorer affinity for either human cytosol or mitochondrial TK's (Km of thymidine to K, of analogue larger than 0.005) and that 5-vinyl-dUrd had a high binding affinity to both viral and human mitochondrial TK's. For instance, the Ki of 5-ethyl-dUrd for human cytosol, human mitochondrial, HSV-1 (strain KOS), and HSV-2 (strain 333) TK's was 82, 305, 0.7, and 0.3 ,uM, respectively. TheKi of 5-vinyl-dUrd for human cytosol, human mitochondrial, HSV-1 (strain KOS), and HSV-2 (strain 333) TK's was 35, 1.7, 0.5, and 0.5 ,iM, respectively (Cheng and Lee, submitted for publication). This communication reports the results of a comparative study on the antiviral and cytotoxic effects of all four analogues and suggests that selective affinity to various TK's is responsible for their differential activity. Some studies on the biological activity of 5-ethyl-, 5-vinyl-, and 5-allyl-dUrd have been reported previously by other investigators (2, 7, 9-11).MATERIALS AND METHODS Cells and viruses. The stock viruses, HSV-1 (strains KOS and B2006) and HSV-2 (strain 333), were kindly given to us by W. Munyon of this institute (1, 3). Both the KOS and 333 strains of herpes simplex viruses but not the B2006 strain cou...

show abstract

mentioning

confidence: 75%

Antiviral Action and Cellular Toxicity of Four Thymidine Analogues: 5-Ethyl-, 5-Vinyl-, 5-Propyl-, and 5-Allyl-2′-Deoxyuridine

Cheng

Domin

Sharma

et al. 1976

Antimicrob Agents Chemother

106

View full text Add to dashboard Cite

show abstract

“…EtdU rd is not very cytotoxic, although it is incorporated into the DNA of mouse (SILAGI et al 1977) and human (SINGH et al 1974;SWIERKOWSKI et al 1973) cells. Chromosome damage was not apparent after such incorporation (SWIERKOWSKI et al 1973;SINGH et al 1974) and the analog was not mutagenic (PIETRZYKOWSKA and SHUGAR 1966;SWIERKOWSKI and SHUGAR 1969).…”

Section: Effects On Normal Cellsmentioning

confidence: 99%

Chemotherapy of Viral Infections

Jones¹

1982

Handbook of Experimental Pharmacology

View full text Add to dashboard Cite

“…EdU does not appear to interfere with regeneration of the epithelium of the rabbit eye (17). EdU has no demonstrable mutagenicity, and the drug does not induce RNA retroviruses in several cell culture systems (20,29,45,48). In rats, more than 90% of the drug or its metabolites are excreted in the kidney within 24 h (24).…”

mentioning

confidence: 99%

Antiviral activity of 5-ethyl-2'-deoxyuridine against herpes simplex viruses in cell culture, mice, and guinea pigs

Schinazi

Scott

Peters

et al. 1985

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The susceptibility of 3 laboratory strains and 24 clinical isolates of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) to 5-ethyl-2'-deoxyuridine was determined in plaque reduction assays in Vero cells. The median effective doses were 8.6 and 7.8 ,M, respectively. The drug was less potent than acyclovir and other related antiviral drugs, but it had a high therapeutic index against both HSV-1 and HSV-2. Drug-resistant viruses were readily produced in cell culture. These variants were cross-resistant to acyclovir, 2'-fluoro-5-iodoaracytosine, and 2'-fluoro-5-methylarauracil but were susceptible to vidarabine or phosphonoformate. These findings confirm that the selective antiviral activity of 5-ethyl-2'-deoxyuridine is mediated by the virus-induced thymidine kinase. Oral or intraperitoneal administration of the drug at nontoxic doses was ineffective in protecting mice against intracerebral challenge with virus. Using implanted osmotic minipumps or coadministering the drug with dimethyl sulfoxide failed to decrease the mortality rate. In guinea pigs infected genitaily with HSV-2, topical drug treatment was more effective than placebo in reducing lesion severity and other clinical and virological variables. These effects were noted whether the drug treatment was initiated 3 or 24 h after infection (ascertained serologically). Drug-treated animals had a significantly lower herpes antibody titer than did placebo-treated guinea pigs, suggesting that the drug can also reduce the viral antigen load. In this model, the drug appeared to be as effective as topical phosphonoformate or acyclovir.5-Ethyl-2'-deoxyuridine (EdU) is a pyrimidine nucleoside with activity in cell culture against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and vaccinia virus (9,16,28,48). The compound is also active in rabbits with herpes keratitis (13, 15), in mice with systemic herpetic infection (7,8), and in dorsally infected guinea pigs (46). Studies in humans have indicated positive effects with this drug for the treatment of ocular herpes (13, 35). EdU does not appear to interfere with regeneration of the epithelium of the rabbit eye (17). EdU has no demonstrable mutagenicity, and the drug does not induce RNA retroviruses in several cell culture systems (20,29,45,48). In rats, more than 90% of the drug or its metabolites are excreted in the kidney within 24 h (24).Since the full spectrum of activity of this drug against HSV is incomplete, several studies were initiated which had the following objectives: (i) delineating the activity of EdU against 2 laboratory strains and 12 clinical isolates of HSV-1 and 1 laboratory strain and 12 clinical isolates of HSV-2; (ii) comparing the cell culture activity of EdU with those of acyclovir (ACV), vidarabine (ara-A), E-5-(2-bromovinyl)-2'-deoxyuridine, 2'-fluoro-5-methylarauracil (FMAU), and 2'-fluoro-5-iodoaracytosine against laboratory strains of HSV; (iii) assessing activities of several of these agents against EdU-resistant variants; (iv) determining the capacity of EdU administered ...

show abstract

5-Ethyl-2?-deoxyuridine: Absence of effects on the chromosomes of human lymphocytes and fibroblasts in culture

Cited by 12 publications

References 7 publications

Antiviral Action and Cellular Toxicity of Four Thymidine Analogues: 5-Ethyl-, 5-Vinyl-, 5-Propyl-, and 5-Allyl-2′-Deoxyuridine

Antiviral Action and Cellular Toxicity of Four Thymidine Analogues: 5-Ethyl-, 5-Vinyl-, 5-Propyl-, and 5-Allyl-2′-Deoxyuridine

Chemotherapy of Viral Infections

Antiviral activity of 5-ethyl-2'-deoxyuridine against herpes simplex viruses in cell culture, mice, and guinea pigs

Contact Info

Product

Resources

About