J. Veselý

5-Azacytidine, a new, highly effective cancerostatic.

Die hohe bakteriostatische und cancerostatische Wirkung eines neuen Antimetaboliten, 5-Azacytidin, wird beschrieben.

Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro.

Several N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) (HPMP) and N-(2-phosphonylmethoxyethyl) (PME) derivatives of purine bases (adenine, guanine, 2-aminoadenine, 3-deazaadenine) and cytosine inhibit the growth of various DNA viruses. PME-derivatives (PMEA, PMEG and PMEDAP) are also active against retroviruses. Both types of nucleotide analogues undergo phosphorylation by cellular nucleotide kinases to their mono- and diphosphates. The phosphorylation with crude extracts of L-1210 cells is potentiated by an ATP-regenerating system. HPMPA is phosphorylated faster than PMEA with or without the ATP-regenerating system. The HPMP and PME analogues inhibit several virus-encoded target enzymes and their cellular counterparts: (1) HSV-1 DNA polymerase is inhibited by the diphosphates of the PME series; the virus-encoded enzyme is more sensitive than HeLa DNA pol alpha and beta. PMEApp terminates the growing DNA chain; it specifically replaces dATP. HPMPApp also acts as an alternative substrate of dATP, but, in contrast with PMEApp, it permits limited chain growth. (2) Diphosphates of both series inhibit HSV-1 ribonucleotide reductase; the greatest inhibition of CDP reduction to dCDP is exhibited by HPMPApp and PMEApp. The enzyme isolated from a PMEA-resistant HSV-1 mutant proved less sensitive to PMEApp, hydroxyurea and HPMPApp. (3) Diphosphates of PME derivatives efficiently inhibit AMV(MAV) reverse transcriptase. (4) The purine HPMP and PME analogues and, even more so, their monophosphate derivatives inhibit purine nucleoside phosphorylase from L-1210 cells.

Prolongation of the lag period preceding the enhancement of thymidine and thymidylate kinase activity in regenerating rat liver by 5-azacytidine

Abstract The administration of 5-azacytidine to rats 1 hr after partial hepatectomy leads to a complete inhibition of thymidine and thymidylate kinase in 24 hr-regenerating liver and to a prolongation of the lag period preceding their increased activity. While 5-azacytidine does not affect DNA synthesis in the liver of sham-operated animals, complete inhibition of its formation in 24 hr-regenerating liver was observed. Inhibition of liver protein synthesis following 5-azacytidine has a different time course and is in agreement with the degradation of liver polyribosomes. Maximal polyribosome degradation and the greatest inhibition of protein synthesis in regenerating liver occur 2–8 hr after 5-azacytidine administration. Decreased thymidine and thymidylate kinase activity in relation to the restored proteosynthetic capacity of the liver after 5-azacytidine administration is discussed.

Effect of 5-azacytidine on developing mouse embryo

5-Azacytidin wurde trächtigen Mäusen am 4.–6. und 11.–13. Tag verabreicht. Bei der ersten Gruppe zeigte sich eine völlige Resorption der Feutusse, während in der zweiten Gruppe hauptsächlich die Leber und das Nervengewebe geschädigt waren. In der ependymalen Zone werden die in Teilung befindlichen Zellen in der Metaphase gestoppt und unterliegen einer pyknotischen Degeneration.

Enhanced uridine kinase and RNA synthesis in regenerating rat liver after 5-azacytidine administration

Abstract The administration of 5-azacytidine to partially hepatectomized rats results in the increase of uridine kinase activity in cell-free liver extracts 24–72 hr after drug administration. At the same time the activity of uridine phosphorylase and of uridine 5′-nucleotidase is decreased, while uridinemonophosphate kinase and uridine 5′-triphosphatase are not affected. The repeated administration of 5-azacytidine leads to a further enhancement of uridine kinase which is 6- to 8-fold higher in 96-hr regenerating livers than in untreated controls. Simultaneously the enhanced incorporation of uridine into liver ribonucleic acids was observed. The metabolic alterations occurring in the liver at later phases after 5-azacytidine in vivo administration are discussed.

High-frequency induction in vivo of mouse leukemia in akr strain by 5-azacytidine and 5-iodo-2'-deoxyuridine.

Nachweis der leukämogenen Wirkung von 5-Azacytidin und 5-Jod-2′-Desoxuridin beim Stamm der AKR-Mäuse. Es wird angenommen, dass es sich hierbei um eine Virusinduktion handelt.

Pycnotic degeneration of ventricular cells in embryonic brain following transplacental exposure to 5-azacytidine.

Das Cytostaticum 5-Azacytidin verursacht 8 bis 12 h nach Applikation Kernpyknosen in den ventrikelnahen Zellschichten des Gehirns bei Mäuseembryonen, ist aber ohne Wirkung auf die Replikation und die Auswanderung der Zellen.

Depressed synthesis of DNA in regenerating rat liver after spinal cord (C7) transection

Nachweis, dass Querschnittläsion des Rückenmarkes in der Höhe C7 bei Ratten nach partieller Hepatektomie zu bedeutender Hemmung der Auswertung von Thymidin für die DNS-Synthese in der regenerierenden Leber führt.

Localization of the labelled 5-azacytidine in cultured mouse embryonic cells

Die Inkorporation des14C-markierten 5-Azacytidins in die embryonalen Mäusefibroblasten, die in Zellkulturen gehalten worden waren, wurde autoradiographisch untersucht. Die Radioaktivität in Kern und Chromosomen ist häufig mit dem Heterochromatin assoziiert. Die Nukleolen werden vergrössert, und die Chromosomen, die sich in der Metaphase befinden, weisen sternförmige Gebilde auf.

Enhancement of rat liver uridine kinase activity by various metabolic inhibitors

Abstract Of 25 compounds tested, eight—namely, 5-azacytidine, gougerotin, cycloheximide, pactamyein, streptovitaein A, adriamyein, daunoruhicin and thioacetamide resulted in the enhancement of liver uridine kinase actiuty in vivo . Puromycin and actinomycin D produced a slight decrease in enzyme activity. With both 5-azaeytidine and cyeloheximide, the enhancement observed was independent of adrenal secretion. Some of the compounds which enhanced hepatic uridine kinase activity 15-azacytidine, cycloheximide and related glutarimide antibioties concomitantly suppressed the activity of the enzyme in the thymus, while daunoruhicin adriamycin and thioacetamide were much less effective in this respect. No relation has been found between the effect of the tested compounds on the incorporation of orotic acid into RNA and the enhanced activity of hepatic uridine kinase.