Incorporation of metabolites of 2'-fluoro-5-iodo-1-β-d-arabinofuranosylcytosine into deoxyribonucleic acid of neoplastic and normal mammalian tissues

Grant, Alan J.; Feinberg, Aaron; Chou, Ting‐Chao; Watanabe, Kyoichi A.; Fox, Jack J.; Philips, Frederick S.

doi:10.1016/0006-2952(82)90349-5

Cited by 36 publications

(13 citation statements)

References 4 publications

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“…Although incorporation of FIAU into total DNA has been previously reported (32,33), it is yet unclear whether FIAU is able to incorporate into mtDNA and whether incorporation of that drug into nucleic acids is predominant in one of the two cellular compartments. In addition, no data are yet available on whether FMAU can also incorporate into either nuclear and mtDNA.…”

Section: Resultsmentioning

confidence: 99%

Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells.

Cui¹,

Yoon²,

Schinazi³

et al. 1995

J. Clin. Invest.

121

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We have explored the mechanism(s) related to FIAU-induced liver toxicity, particularly focusing on its effect on mitochondrial function in a human hepatoma cell lineHepG2. The potential role of FMAU and FAU, metabolites detected in FIAU-treated patients were also ascertained. FIAU and FMAU inhibited cell growth and were effectively phosphorylated. A substantial increase in lactic acid production in medium of cells incubated with 1-10 ,uM FIAU or FMAU was consistent with mitochondrial dysfunction. Slot blot analysis demonstrated that a two week exposure to 10 ,uM FIAU or FMAU was not associated with a decrease in total mitochondrial (mt) DNA content. However, FIAU and FMAU were incorporated into nuclear and mtDNA and relative values suggest that both compounds incorporate at a much higher rate into mtDNA. Electron micrographs of cells incubated with 10 ,IM FIAU or FMAU revealed the presence of enlarged mitochondria with higher cristae density and lipid vesicles. In conclusion, these data suggest that despite the lack of inhibition of mtDNA content, incorporation of FIAU and FMAU into mtDNA of HepG2 cells leads to marked mitochondrial dysfunction as evidenced by disturbance in cellular energy metabolism and detection of

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Section: Resultsmentioning

confidence: 99%

Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells.

Cui¹,

Yoon²,

Schinazi³

et al. 1995

J. Clin. Invest.

121

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“…In mice, integration of FIAU into cellular DNA after single doses of radioactive drug was highest in tissues with the most rapidly dividing cells. [44][45][46] In studies of monkeys, rats, and dogs treated with FIAU, significant integration of FIAU was observed into cellular DNA in all three species. 9 In rats, the liver appeared to be a minor target for FIAU integration after 1 day, but after 77 days of FIAU treatment, the FIAU content of hepatic DNA was higher than the DNA of any other tissue.…”

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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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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“…FIAU has been detected in the tissues and DNA of mice following acute intraperitoneal administration of radiocarbonlabeled 1-(2'-deoxy-2'-fluoro-3-D-arabinofuranosyl)-5-iodocytosine (5,22). Recently, FIAU was found to accumulate in the DNAs of several different animal species following chronic oral administration (40).…”

Section: Discussionmentioning

confidence: 99%

Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers

Bowsher

Compton

Kirkwood

et al. 1994

Antimicrob Agents Chemother

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Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125j]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coeflicients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids.Fialuridine (FIAU), 1-(2'-deoxy-2'-fluoro-13-D-arabinofuranosyl)-5-iodouracil (Fig. 1, compound 2), is one of a series of 2'-fluoro-substituted arabinosyl pyrimidine nucleosides that have demonstrated potent antiviral activities against a number of clinically important viruses, including hepatitis B virus (HBV) (7,11,28,47). Analogs of FIAU have been shown to inhibit viral replication in the woodchuck and duck models of HBV infection (18,19). Although the mechanism of the anti-HBV activity is not well understood, evidence suggests that the triphosphate analog of FIAU is a potent inhibitor of HBV DNA polymerase activity (17,23,43). During early clinical investigation FIAU showed much promise as an anti-HBV drug because it markedly reduced the level of HBV DNA in the serum of patients with chronic hepatitis B (20). However, clinical trials were terminated after adverse events occurred following oral administration of FIAU (0.1 and 0.25 mg/kg of body weight per day) for more than 2 months (24, 29). The mechanism of the unexpected delayed toxicity is unresolved.Prior to the termination of clinical trials an assay was needed to quantify FIAU in biological fluids. However, the anticipated low therapeutic dose in patients necessitated the development of a highly sensitive analytical method. The criterion of sensitivity precluded the use of an existing UV-based high-pressure liquid chromatographic (HPLC) method for FIAU because its

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Incorporation of metabolites of 2'-fluoro-5-iodo-1-β-d-arabinofuranosylcytosine into deoxyribonucleic acid of neoplastic and normal mammalian tissues

Cited by 36 publications

References 4 publications

Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells.

Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells.

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

Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers

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