Biochemical pharmacology of (+)- and (-)-2',3'-dideoxy-3'-thiacytidine as anti-hepatitis B virus agents.

Chang, C.N.; Skalski, Violetta; Zhou, Jifu; Cheng, Yung‐Chi

doi:10.1016/s0021-9258(18)41687-0

Cited by 189 publications

(22 citation statements)

References 17 publications

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“…A substantially higher therapeutic window between 50% cytotoxic and 50% viral inhibitory concentrations has also been observed for FZD versus zidovudine in a variety of cell lines [39]. However, the in vitro results also demonstrated a similar or lower anti-HIV activity for FZD than for zidovudine itself, consistent with Phase II trial results [40] that showed a week-4 viral load reduction for 600 mg FZD twice daily (-0.67 log 10 copies/ml) that was similar to earlier 4-week results for 200 mg zidovudine three times daily [23] range) [24] and subsequent phosphorylation by additional human cellular kinases (including cytidinemonophosphate kinase) [17,25,26] [41]. This surprisingly low potency for a nucleotide analogue in vitro and in vivo may reflect monophosphorylation not being the rate-limiting step in the activation of zidovudine.…”

Section: Nucleotide Analogues and Prodrugssupporting

confidence: 83%

An Introduction to Nucleoside and Nucleotide Analogues

Squires

2000

Antiviral Therapy

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The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain the complete suppression of HIV replication required for extended therapy, and both suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the more potent drug classes used with them. However, it has become apparent in recent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safely used. An independent contribution to peripheral fat wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of several NRTI agents for uptake by mitochondrial DNA polymerase γ, has been demonstrated both in vitro and in vivo. New chain-terminating agents are urgently needed that address issues of improved virological potency, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, currently in Phase III clinical trials. This agent has shown high potency and an unusually durable response in trials of single-agent therapy intensification in highly treatment-experienced individuals, and its active metabolite, tenofovir diphosphate, exhibits a long intracellular half-life in both resting and activated peripheral blood mononuclear cells that permits once daily dosing. Tenofovir diphosphate also exhibits a very low affinity for DNA polymerase γ in vitro, suggesting a low degree of in vivo mitochondrial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF and other NtRTIs as ‘second-generation’ nucleoside analogues carefully evaluated for potential long-term toxicity, can be expected to significantly improve the therapeutic options for both those currently on HAART and those yet to begin.

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Section: Nucleotide Analogues and Prodrugssupporting

confidence: 83%

An Introduction to Nucleoside and Nucleotide Analogues

Squires

2000

Antiviral Therapy

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“…Potent inhibition of the activities of HIV reverse transcriptase (9,18) and HBV DNA polymerase (32) by 3TC-TP supports the view that the 5Ј-triphosphate metabolite of 3TC accounts for the antiviral activity of that agent. Similarly, weak inhibition of mammalian DNA polymerases ␣ and ␤ by 3TC-TP (9,18) suggests that the moderate cytotoxicity of 3TC is also attributable to that nucleotide metabolite. In the present study, we measured the intracellular stabilities of 5Ј-phosphates of 3TC and tested tactics aimed at increasing the intracellular concentrations of these metabolites.…”

Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 99%

“…␤-L-(Ϫ)-2Ј,3Ј-Dideoxy-3Ј-thiacytidine (3TC) is a cytosine nucleoside analog that potently inhibits the replication of human immunodeficiency virus (HIV) (11,30), as well as human hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) (9,12). Inside mammalian cells, 3TC is sequentially phosphorylated by deoxycytidine kinase (9,17,33) and pyrimidine nucleotide kinases to form 3TC 5Ј-triphosphate (3TC-TP), which inhibits viral reverse transcriptase and DNA polymerase activities (9,18,32). 3TC-TP is incorporated into HIV proviral DNA, resulting in chain termination (18); similarly, as a chain terminator, the 5Ј-triphosphate metabolite inhibits both the reverse transcriptase and the DNA polymerase activities of the DHBV polymerase (32).…”

mentioning

confidence: 99%

“…3TC-TP is incorporated into HIV proviral DNA, resulting in chain termination (18); similarly, as a chain terminator, the 5Ј-triphosphate metabolite inhibits both the reverse transcriptase and the DNA polymerase activities of the DHBV polymerase (32). The low cellular toxicity of 3TC (10,31,35) has been attributed to a weak interaction of 3TC-TP with cellular DNA polymerases (9,18). 3TC has been tested in phase I/II clinical studies with HIV-infected patients (30,37) and is currently under evaluation in studies with HBV-infected patients.…”

mentioning

confidence: 99%

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Modulation of the metabolism of beta-L-(-)-2',3'-dideoxy-3'-thiacytidine by thymidine, fludarabine, and nitrobenzylthioinosine

Rahn

Kieller

Tyrrell

et al. 1997

Antimicrob Agents Chemother

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beta-L-(-)-2',3'-Dideoxy-3'-thiacytidine (3TC) is a cytosine nucleoside analog that potently inhibits the replication of human and duck hepatitis B viruses and human immunodeficiency virus through the activity of its 5'-triphosphate ester metabolite. The present study examined the intracellular decay of 3TC 5'-phosphates and tested strategies for modulating the cellular content of those nucleotides in primary cultures of duck hepatocytes and in human hepatoma 2.2.15 cells and CCRF-CEM T lymphoblasts. Inhibition by deoxycytidine of the 5'-phosphorylation of 3TC in duck hepatocytes confirmed that, as in mammalian cells, deoxycytidine kinase catalyzed 3TC activation. The 5'-mono, 5'-di-, and 5'-triphosphates of 3TC underwent monoexponential elimination from duck hepatocytes and 2.2.15 cells (half-lives, 3.6 to 8.0 h). Thymidine and fludarabine, which are agents that enhance the activity of deoxycytidine kinase, were tested in strategies for increasing the cellular content of 3TC 5'-phosphates. Coordinate treatment of cells with 3TC and thymidine (50 microM) increased the content of 3TC 5'-monophosphate in duck hepatocytes and the content of 3TC 5'-di- and 5'-triphosphates in 2.2.15 cells, but enhancement of 3TC 5'-phosphate levels in CCRF-CEM cells required a higher thymidine concentration (100 microM). Fludarabine (5 microM) did not affect the contents of 3TC 5'-di- and 5'-triphosphates in duck hepatocytes, but modestly increased the contents of those nucleotides in 2.2.15 cells and CCRF-CEM cells. Nitrobenzylthioinosine (NBMPR), an inhibitor of the es facilitated diffusion nucleoside transporter, reduced the level of entry of 3TC into 2.2.15 cells and abolished inward fluxes of thymidine, adenosine, and deoxycytidine. In 2.2.15 cells and CCRF-CEM cells, NBMPR reduced the formation of 3TC 5'-di- and 5'-triphosphates and reversed the thymidine- and fludarabine-induced increases in the formation of those nucleotides. NBMPR protected against the cytotoxicity of 3TC in CCRF-CEM cells, whereas thymidine potentiated that toxicity, apparently by enhancing the formation of 3TC 5'-triphosphate. Taken together, these results indicate that deoxycytidine kinase and the es nucleoside transporter are targets for manipulation of the metabolism and activity of 3TC.

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Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy

et al. 1999

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Hepatitis B virus (HBV) reactivation has been described in cancer patients who received cytotoxic/immunosuppressive therapy and may result in liver damage of varying degrees of severity. There is no known effective treatment. Lamivudine, a nucleoside analogue, has been found to suppress HBV replication and to improve histology in chronic carriers of hepatitis B virus. The outcome of lamivudine therapy (at doses of 100 or 150 mg/day) in eight patients who developed HBV reactivation while receiving cytotoxic chemotherapy is described. Each of the eight patients had >98% suppression of the pretreatment HBV DNA levels. Three of the five patients who were initially HBeAg positive underwent seroconversion. Five patients had normalization of liver function tests and improvement in clinical condition. However, one patient died of hepatic failure due to HBV-related submassive liver necrosis, and two died of widespread metastases (including liver) from the primary malignancies. It is concluded that early commencement, i.e., at the onset of HBV reactivation before severe hepatic decompensation, of lamivudine may be effective in the control of HBV reactivation during chemotherapy. In Hong Kong, where hepatitis B infection is endemic, we propose to screen all cancer patients for hepatitis B surface antigen before immunosuppressive/cytotoxic therapy, and to closely monitor liver function of those who are found to be HBsAg seropositive.

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Biochemical pharmacology of (+)- and (-)-2',3'-dideoxy-3'-thiacytidine as anti-hepatitis B virus agents.

Cited by 189 publications

References 17 publications

An Introduction to Nucleoside and Nucleotide Analogues

An Introduction to Nucleoside and Nucleotide Analogues

Modulation of the metabolism of beta-L-(-)-2',3'-dideoxy-3'-thiacytidine by thymidine, fludarabine, and nitrobenzylthioinosine

Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy

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