BACKGROUND: The archetypal DNA methyltransferase inhibitors, 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) are potent antineoplastic agents used in the treatment of mainly, blood malignancies. However, the administration of these drugs is confounded by their hydrolytic lability which decreases plasma circulation time. Here, we describe a new biodegradable, polyanhydride formulation for drug delivery that circumvents this drawback. METHODS: Injectable/implantable polymeric microbeads containing dispersed microcrystals of hydrophilic AZA or DAC packed in a dry environment are protected from hydrolysis, until the hydrolytic zone reaches the core. Diclofenac is embedded into the formulation to decrease any local inflammation. The efficacy of the formulations was confirmed by monitoring the induced demethylation, and cytostatic/cytotoxic effects of continuous drug release from the time-course dissolution of the microbeads, using an in vitro developed cell based reporter system. RESULTS: Poly(sebaccic acid-co-1,4-cyclohexanedicarboxylic acid) containing 30 wt. % drug showed zero-order release (R(2) = 0.984 for linear regression), and release rate of 10.0 %/h within the first 5 h, and subsequent slower release of the remaining drug, thus maintaining the level of drugs in the outer environment considerably longer than the typical plasma half-life of free azanucleosides. At lower concentrations, the differences between powder drug formulations and microbeads were very low or negligible, however, at higher concentrations, we discovered equivalent or increasing effects of the drugs loaded in microbeads. CONCLUSIONS: The study provides evidence that microbead formulations of the hydrolytically labile azanucleoside drugs could prevent their chemical decomposition in aqueous solution, and effectively increase plasma circulation time.
- MeSH
- antimetabolity antitumorózní aplikace a dávkování farmakologie MeSH
- azacytidin aplikace a dávkování analogy a deriváty farmakologie MeSH
- implantabilní infuzní pumpy MeSH
- kultivované buňky MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- mikrosféry MeSH
- polymery chemie MeSH
- vstřebatelné implantáty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This review summarizes the basic milestones of the research of 5-azacytosine nucleosides chronologically from their discovery and anticancer activity identification, through to subsequent unveiling of their mechanism of action based on DNA hypomethylation and tumor-suppressor gene reactivation, to the final US FDA approval of 5-azacytidine (Vidaza(®)) and 2'-deoxy-5-azacytidine (Dacogen(®)) for the treatment of myelodysplastic syndromes. 5,6-dihydro-2'-deoxy-5-azacytidine, a compound with anti-HIV activity through lethal mutagenesis, representing a unique mechanism of action among existing anti-retroviral drugs, is discussed together with quite recent discovery of its so far unexpected hypomethylation activity. Special attention is paid to 5-azacytosine acyclic nucleoside analogues and phosphonomethyl derivatives with the emphasis on the new potent anti-DNA virus agent (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine and its prodrug forms. Considering the potential pharmaceutical applications, 5-azacytosine and 5,6-dihydro-5-azacytosine appear to be so far the most effective cytosine mimics for the design of novel antiviral and anti-tumor drug candidates.
- MeSH
- antitumorózní látky chemie farmakologie terapeutické užití MeSH
- azacytidin analogy a deriváty chemie farmakologie terapeutické užití MeSH
- cytosin analogy a deriváty chemie farmakologie terapeutické užití MeSH
- HIV infekce farmakoterapie MeSH
- HIV účinky léků MeSH
- látky proti HIV chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- metylace DNA účinky léků MeSH
- nádory farmakoterapie MeSH
- objevování léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
3- and 8-(8-phosphonooctyl)-8-aza-7,9-dideazaxanthine, and 1,8-bis(8-aza-7,9-dideazaxanthin-8-yl)octane were prepared and found to inhibit thymidine phosphorylase from Escherichia coli, human recombinant TP expressed in V79, and TP purified from human placenta. The IC(50) values ranged from 3.5 to 27μM.
- MeSH
- Escherichia coli enzymologie MeSH
- inhibitory enzymů chemie farmakologie MeSH
- lidé MeSH
- placenta enzymologie MeSH
- pyrimidinony chemie farmakologie MeSH
- pyrroly chemie farmakologie MeSH
- rekombinantní proteiny antagonisté a inhibitory metabolismus MeSH
- těhotenství MeSH
- thymidinfosforylasa antagonisté a inhibitory metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In this paper, we have compared hypomethylating ability of classical beta-d-anomer of 5-aza-2'-deoxycytidine (5-aza-CdRf) and its alpha anomer in cell cultures. Alpha anomers of nucleosides generally exhibit low biological activity compared to their beta counterparts. It is reported that alpha anomer of 5-aza-CdRf efficiently hypomethylated genomic DNA in human T-lymphoblastoid CCRF-CEM cells. Satellite 2 and 18S rDNA were hypomethylated by alpha anomer at concentrations comparable to the beta form. However, the toxicity of the alpha anomer was 4-fold less than that of beta form. Contrast to CCRF-CEM the A549 lung carcinoma cells, possessing negligible level of methylation at repetitive loci, were highly resistant to 5-aza-CdRf treatment suggesting that global genomic methylation might be needed to mediate cytotoxic effect of the drug. Possible mechanisms of inhibition of DNA methylation by alpha anomer are discussed. In conclusion, alpha anomer of 5-aza-CdRf displaying lower host cytotoxicity than the classical beta form may be of potential use in epigenetic therapy.
- MeSH
- antimetabolity farmakologie MeSH
- apoptóza účinky léků MeSH
- azacytidin analogy a deriváty farmakologie MeSH
- DNA sondy MeSH
- financování organizované MeSH
- isomerie MeSH
- lidé MeSH
- metylace DNA účinky léků MeSH
- nádorové buněčné linie MeSH
- Southernův blotting MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
The inhibitory and/or substrate activity of 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine [(S)-HPMPC, cidofovir, Vistide™] diphosphate towards eukaryotic DNA polymerases α, δ and ε* was examined. Cidofovir diphosphate is a weak competitive inhibitor of the above enzymes, approximately 3 to 7 times weaker than its adenine analogue (S)-HPMPApp. The enzymes also catalyze incorporation of (S)-HPMPC into DNA; after insertion of one (S)-HPMPC residue into DNA, another dNMP residue may incorporate. DNA polymerase δ and ε* can successively accommodate in the growing chain two (S)-HPMPC residues at the maximum, whereas pol α up to three residues.
