Kinetic analysis of the interaction between the diphosphate of (S)-1-(3-hydroxy-2-phosphonylemthoxypropyl)cytosine, ddCTP, AZTTP, and FIAUTP with human DNA polymerases β and γ

Cherrington, Julie M.; Allen, S. J. W.; McKee, Blaine H.; Chen, Ming S.

doi:10.1016/0006-2952(94)90600-9

Cited by 59 publications

(38 citation statements)

References 8 publications

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“…First, dideoxycytidine (ddC), a known inhibitor of the DNA repair enzyme pol ␤, 23,24 was used to inhibit DNA repair synthesis in CLL cells in the presence and absence of F-ara-A. Addition of 30 M ddC reduced the repair synthesis by approximately 80% (Figure 2a), whereas cell survival was not affected by this drug concentration (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine

et al. 2000

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Section: Resultsmentioning

confidence: 99%

Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine

et al. 2000

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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%

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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“…It is, however, 10 times more potent than AZT, and does not have the same toxicity profile, and does not show cross-resistance; the reason why it has been extensively studied in monotherapy or in combination with AZT (25). It is known to reduce the activity of the DNA polymerase beta and inhibit the mitochondria1 DNA polymerase gamma (14). The S-phase accumulation observed might be an illustration of this effect on DNA polymerase.…”

Section: Discussionmentioning

confidence: 94%

“…On the other hand, the triphosphate of ddC (ddCTP) ha3 been shown to inhibit DNApolymerase gamma and beta resulting in a n impact at the level of mitochondria1 DNA synthesis and DNA repair respectively (14). Therefore we decided to test this deoxycytidine derivative as a BRM, and to investigate the effect of exposure duration and concentration.…”

Section: -1 86xmentioning

confidence: 99%

“…Biparametric analysis revealed progresssive accumulation of cells in the late S-phase especially at 72 h, although a significant global S-phase accumulation had already occurred at 48 h. The increase in radiation sensitivity and S-phase accumulation seems contradictory (30). It is as yet unclear whether the S-phase accumulation may be a result of direct interaction of ddC with thymidine kinase (TIC) which is required in cell proliferation or by inhibition of DNA polymerase gamma (14,31). On the other hand, the known inhibitory effect on DNA polymerase beta and hence the reduction of DNA repair may explain the marked change in the alpha component of the dose response.…”

Section: )mentioning

confidence: 99%

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Cell Line Specific Radiosensitizing Effect of Zalcitabine (2',3'-dideoxycytidine)

Coucke

Copaceanu

et al. 1997

Acta Oncologica

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Kinetic analysis of the interaction between the diphosphate of (S)-1-(3-hydroxy-2-phosphonylemthoxypropyl)cytosine, ddCTP, AZTTP, and FIAUTP with human DNA polymerases β and γ

Cited by 59 publications

References 8 publications

Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine

Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine

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

Cell Line Specific Radiosensitizing Effect of Zalcitabine (2',3'-dideoxycytidine)

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