5-Azacytidine (NSC-102 816) was prepared synthetically and independently isolated from the culture filtrate of Streptoverticillium ladakanus. It is an s-triazine analogue of cytidine possessing a broad spectrum of biological effects. In mammalian tissue it is phosphorylated to 5-azacytidine 5´-phosphates and incorporated into different species of RNAs and into DNA. 5-Azacytidine 5´-monophosphate inhibits orotidine 5´-phosphate decarboxylase blocking thus the de novo pyrimidine synthesis. Following the administration of 5-azacytidine a rapid breakdown of liver polyribosomes has been observed; furthermore, in different systems a profound inhibitory effect of the drug on the maturation of ri-bosomal RNA has been found. 5-Azacytidine interferes with different induced liver enzymes ; in some cases their activity is elevated since the rate of enzyme degradation is decreased. The cytostatic effect of the drug is directed primarily against lymphatic leukemia although some recent reports indicate its action also against human solid tumours. Chemotherapy of leukemic mice by 5-azacytidine results simultaneously in the depressed synthesis of liver and spleen polyamines. 5-Azacytidine exhibits further mutagenic, abortive, immunosuppressive, antimitotic, radioprotective and virostatic effects. The drug also affects DNA and protein synthesis in embryonic tissues, cells in tissue culture, regenerating livers, in bacteria and phages. The changes associated with the emergence of resistance towards 5-azacytidine are associated with the decreased activity of uridine kinase in mouse leukemia cells. On the contrary, in adult rat livers 5-azacytidine administration leads to the increased activity of this enzyme. Different authors have used 5-azacytidine as a tool for the study of biochemical mechanisms connected with a cell proliferation and division.
The development of resistance of leukemic AKR mice to 5-azacytidine administered in small doses was investigated. The activity of uridine kinase decreased simultaneously with the development of resistance. The gradual shortening of the survival time of treated animals and the depression of enzyme activity had a continuous character. The application of 5-azacytidine along with hydrocortisone or actinomycin D did not appreciably afect the development of resistance. In leukemic cells resistant to 5-azacytidine the incorporation of uridine, cytidine and 5-azacytidine itself into ribonucleic acids was depressed in accordance with the impaired anabolic transformations of 5-azacytidine in vivo as well as with the soluble fraction in vitro.5-Azacytidine which has been synthesized in!?% The purpose of the present report was to these laboratories (Piskala and Sorm, 1964)' investigate the pyrimidine metabolism of mouse has potent biological effects; its antileukemic leukemic cells made resistant to 5-azacytidine. properties in mouse leukemia are particularly It was of interest to find out whether a correlation pronounced (Sorm and Veseli, 1964; Cihlk and existed between the development of resistance Veselg and Sorm, 1965). Preliminary and the uridine kinase activity which is responclinical trials revealed that 5-azacytidine might sible for the phosphorylation of 5-azacytidine be suitable for therapeutic application. (JurovEik et al., 1965). Like 5-fluorouracil (Chaudhuri et al., 1958; Reichard et al., 1961), 6-azauridine (Habermann andSorm, 1958;Pasternak et al., 1961), Reagents. 5-Azacytidine was synthesized by
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