Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts.

Lewis, William; Levine, Eric S.; Griniuviene, B.; Tankersley, Kevin O.; Colacino, Joseph M.; Sommadossi, Jean‐Pierre; Watanabe, Kyoichi A.; Perrino, Fred W.

doi:10.1073/pnas.93.8.3592

Cited by 157 publications

(101 citation statements)

References 27 publications

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“…[33][34][35] ddC and FIAU both are competitive inhibitors of DNA polymerase ␥ with very low K i . [38][39][40][41] Because ddC lacks the 3Ј-OH group necessary for DNA chain extension, incorporation of ddC into DNA results in obligatory chain termination and inhibition of mtDNA synthesis. Unlike dideoxynucleosides, FIAU has a functional 3Ј-OH group that allows chain extension and incorporation of FIAU into mitochondrial 35,38 and nuclear 36,37,39 DNA.…”

Section: Discussionmentioning

confidence: 99%

“…[38][39][40][41] Because ddC lacks the 3Ј-OH group necessary for DNA chain extension, incorporation of ddC into DNA results in obligatory chain termination and inhibition of mtDNA synthesis. Unlike dideoxynucleosides, FIAU has a functional 3Ј-OH group that allows chain extension and incorporation of FIAU into mitochondrial 35,38 and nuclear 36,37,39 DNA. It may follow that alterations of mitochondrial function and structure, at least in short-term in vitro studies, are the result of altering the genetic cascade within mitochondria.…”

Section: Discussionmentioning

confidence: 99%

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Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

et al. 1998

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Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2Јdeoxy-2Јfluoro-1-␤-Darabinofuranosyl-5-iodo-uracil). In an initial experiment, groups of six chronic woodchuck hepatitis virus (WHV) carrier woodchucks received daily doses of FIAU by intraperitoneal injection for 4 weeks. At 0.3 mg/kg/d, the antiviral effect was equivocal, but at 1.5 mg/kg/d, FIAU had significant antiviral activity. No evidence of drug toxicity was observed during the 4-week period of treatment or during posttreatment follow-up. In a second experiment, groups of nine WHV carriers or uninfected woodchucks were given 1.5 mg/kg/d of FIAU orally for 12 weeks, and the results compared with placebo-treated controls. After 4 weeks, the serum WHV-DNA concentration in the FIAUtreated carrier group was two to three logs lower than that in the placebo-treated group. After 12 weeks of FIAU treatment, serum WHV DNA was not detectable by conventional dot-blot analysis, hepatic WHV-DNA replicative intermediates (RI) had decreased 100-fold, and hepatic expression of WHV core antigen was remarkably decreased. No evidence of toxicity was observed after 4 weeks, but, after 6 to 7 weeks, food intake decreased and, after 8 weeks, the mean body weights of woodchucks treated with FIAU were significantly lower than controls. Anorexia, weight loss, muscle wasting, and lethargy became progressively severe, and all FIAU-treated woodchucks died or were euthanized 78 to 111 days after treatment began. Hepatic insufficiency (hyperbilirubinemia, decreased serum fibrinogen, elevated prothrombin time), lactic acidosis, and hepatic steatosis were characteristic findings in the final stages of FIAU toxicity in woodchucks. The syndrome of delayed toxicity in woodchucks was similar to that observed previously in humans treated with FIAU, suggesting that the woodchuck should be valuable in future investigations of the molecular mechanisms of FIAU toxicity in vivo and for preclinical toxicological evaluation of other nucleoside analogs before use in patients. (HEPATOLOGY 1998;28:179-191.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

et al. 1998

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“…12,13 Finally, the use of FIAU as an antiviral agent in human patients led to severe toxicity 23 and it has been banned. FIAU toxicity in cells not expressing HSV-TK is mainly due to FIAU phosphorylation by mitochondrial TK 25 and the incorporation of FIAU triphosphate into mitochondrial DNA by DNA polymerase gamma. 13,25 LT can be phosphorylated by mitochondrial TK, 26 but to a much lesser extent than its natural D enantiomer.…”

Section: Discussionmentioning

confidence: 99%

“…FIAU toxicity in cells not expressing HSV-TK is mainly due to FIAU phosphorylation by mitochondrial TK 25 and the incorporation of FIAU triphosphate into mitochondrial DNA by DNA polymerase gamma. 13,25 LT can be phosphorylated by mitochondrial TK, 26 but to a much lesser extent than its natural D enantiomer. However, because of its L conformation, the triphosphate derivative is a very poor substrate for nuclear and mitochondrial DNA polymerases, 27,28 and does not cause any sign of mitochondrial toxicity even after prolonged treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Once the unnatural L-thymidine monophosphate is formed inside the cells, di-and triphosphates are generated by poorly characterized membrane-bound kinases. 18,19 b-L-Nucleotides are very poor-or nonsubstrates for mammalian DNA polymerases 24,25 and remain trapped inside the cell because their increased charge inhibits their passive leakage. As previously shown in HeLa cells, most of the radioactivity is associated with 3 H-LT mono-, di-and triphosphates.…”

Section: Autoradiography Distinguishes Hsv-tk-positive From Hsv-tk-nementioning

confidence: 99%

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Lack of enantioselectivity of herpes virus thymidine kinase allows safer imaging of gene delivery

et al. 2003

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Herpes simplex virus thymidine kinase (HSV-TK) is widely used in gene therapy. The enzymatic activity of HSV-TK may be traced in vivo by specific radiopharmaceuticals in order to image transgene expression. However, most of these radiopharmaceuticals are toxic per se or after activation by HSV-TK, and therefore do not represent ideal molecules for clinical applications and repeated imaging. Unlike human cytosolic TK, HSV-TK is not enantioselective and can efficiently phosphorylate both D and L enantiomers of b-thymidine. Here we show that, after phosphorylation by HSV-TK, tritiated L-b-thymidine (LT) is selectively retained inside the cells in vitro and in vivo. We used the in vivo accumulation of radioactive phosphorylated LT to image the HSV-TK-positive cells inside a transplantable murine brain tumour after inoculation of cells producing retroviruses carrying HSV-TK. Owing to their unnatural enantiomeric conformation, phosphorylated LT metabolites are very poorly processed by mammalian enzymes, thus leading to increased cellular retention and minimal toxicity. The ability to image cells expressing the HSV-TK gene by using radiolabelled LT, without damaging the cells accumulating the phosphorylated L-nucleoside, will be important to monitor the levels and spatial distribution of therapeutic vectors carrying HSV-TK.

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Antiviral Agents, DNA

Middleton

Rockway

2003

Burger's Medicinal Chemistry and Drug Discovery

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The seven families of DNA viruses that cause disease in humans show tremendous variety in the relationships that they have with their hosts. This variety is reflected both in the disease states that they cause and the approaches used to develop antiviral drugs to treat them. The most successful antiviral tools have been nucleoside analogs, particularly those targeting the polymerases of herpesviruses and hepatitis virus B. The list of nucleoside analog drugs continues to expand as compounds are developed with greater potency or range, better bioavailability, or improved side effect profiles. Other viral targets have started to receive more attention, including helicases, proteases, and enzymes required for virion assembly. These targets should gain in importance as resistance to currently available drugs becomes more prevalent. In addition, expanding the list of viable viral targets is particularly important with regard to members of the parvovirus, papillomavirus, and polyomavirus families, which do not encode a viral polymerase. Some effective antiviral treatments have not targeted the virus but rather the immune response to the viral infection. An optimal immune response is critical to elimination of some classes of viruses, and exploiting this aspect of the host‐virus interaction provides another approach to antiviral drug development.

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Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts.

Cited by 157 publications

References 27 publications

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

Lack of enantioselectivity of herpes virus thymidine kinase allows safer imaging of gene delivery

Antiviral Agents, DNA

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