Disease relevance of Pyrazomycin

• Rat hepatomas: chemotherapy with lycurim and pyrazofurin [1].
• Synergistic effect of purine derivatives on the toxicity of pyrazofurin and 6-azauridine towards cultured mammalian cells [2].
• Of the compounds studied, pyrazofurin and 3-deazaguanine emerged as more potent inhibitors of respiratory syncytial virus than ribavirin [3].
• Pyrazofurin is one of four naturally occurring C-nucleoside antibiotics; it is elaborated by Streptomyces candidus [4].
• Sequential combination of pyrazofurin and 5-azacytidine in patients with acute myelocytic leukemia and carcinoma [5].

High impact information on Pyrazomycin

• Because hepatoma 8999 had a high adenosine kinase activity, the effect of Pyrazofurin (PF; 3-beta-D-ribofuranosyl-4-hydroxypyrazole-5-carboxamide) was examined in vitro: The LD50 was 8.5 X 10(-8) M in a 6-hour exposure [1].
• 3-Deazauridine lowered dCTP and stimulated ara-C uptake; however, pyrazofurin and glucosamine were potent inhibitors of ara-C uptake although they also decreased dCTP levels [6].
• Kinetics of N-(phosphonacetyl)-L-aspartate and pyrazofurin depletion of pyrimidine ribonucleotide and deoxyribonucleotide pools and their relationship to nucleic acid synthesis in intact and permeabilized cells [7].
• Phase and cell cycle specificity of pyrazofurin action [8].
• Inhibition of de novo pyrimidine nucleotide and DNA synthesis and growth of cultured Novikoff rat hepatoma cells and other cell lines by pyrazofurin (NSC 143095) [9].

Chemical compound and disease context of Pyrazomycin

• Rat hepatoma cells that have undergone stepwise selection in increasing concentrations of pyrazofurin have coordinately increased levels of both orotate phosphoribosyltransferase (EC 2.4.2.10) and orotidine-5'-phosphate decarboxylase (EC 4.1.1.23) activity [10].
• A novel synergistic effect of several purine derivatives such as adenine, adenosine, hypoxanthine, and guanine on the toxicity of nucleoside analogs pyrazofurin and 6-azauridine towards cultured Chinese hamster ovary (CHO) cells has been observed [2].
• Inhibitors of these enzymes (VF-122, acivicin, pyrazofurin) and that of IMP dehydrogenase (tiazofurin) efficiently killed hepatoma 3924A cells in culture, as demonstrated by the clonogenic assay [11].
• Ribavirin, amantadine, pyrazofurin, and glycyrrhizin emerged, from the present study, as promising candidates for chemotherapy of acute hepatitis A [12].
• Comparison of the anti-respiratory syncytial virus activity and toxicity of papaverine hydrochloride and pyrazofurin in vitro and in vivo [13].

Biological context of Pyrazomycin

• These data indicate that gene amplification is the major factor contributing to the enzyme overproduction in the pyrazofurin-resistant cells [14].
• Phosphorylation of unprotected 4 with POCl3 and subsequent debenzylation of the intermediate 17 gave pyrazofurin 5'-phosphate (18), which provided the first chemical synthesis of 18 [15].
• 5-Amino-3-beta-D-ribofuranosylpyrazolo[3,4-e][1,3]oxazin-7-o ne has been synthesized via cyclization of the appropriately protected pyrazofurin derivatives and subsequent transformations of the heterocyclic moiety [16].
• The enrichment of carbons 3, 4, and 5 of pyrazofurin from [2-13C]acetate by S. candidus confirms earlier findings that acetate is converted to glutamate by the combined action of the Krebs cycle and malic enzyme [Elstner, E. F., Suhadolnik, R. J., & Allerhand, A. (1973) J. Biol. Chem. 248, 5385] [4].
• Cytidine, which can be deaminated to uridine, will substitute for uridine to maintain normal cell growth in the presence of growth-inhibitory concentrations of pyrazofurin (5 microM) [17].

Anatomical context of Pyrazomycin

• Pyrazofurin (PYF), a C-riboside, inhibited the replication of cultured Novikoff rat hepatoma cells, HeLa cells, and mouse L-cells at concentrations as low as 0.1 to 10 muM, but Novikoff cells were more sensitive than the cells of the other two cell lines [9].
• Instead, these findings indicate that the primary mechanism for exogenous Urd reversal of pyrazofurin inhibition of DNA synthesis involves the reversal of pyrazofurin inhibition of UMP synthase, thus restoring orotic acid incorporation into lymphocyte DNA through the pyrimidine de novo pathway [18].

Associations of Pyrazomycin with other chemical compounds

• Cells resistant to pyrazofurin and 6-azauridine have been selected from a simian virus 40-transformed Syrian hamster line and from a Chinese hamster lung line [19].
• In searching for derivatives of pyrazofurin that could display antiviral properties by means that do not require C-5' phosphorylation, 5'-deoxypyrazofurin (3) has been synthesized in six steps from methyl5-deoxy-2,3-O-isopropylidene-beta-D-ribofuranoside (4) [20].
• Carbon-13 incorporation into pyrazofurin was observed by proton-decoupled 13C Fourier transform NMR spectroscopy [4].
• This technique has been used to generate dose-response curves describing the effects of mycophenolic acid and pyrazofurin on individual colonies of Chinese hamster ovary cells [21].
• Experiments in tissue culture and in solid tumors utilizing treatment schedules with pyrazofurin in combination with galactosamine, and the use of adriamycin, succeeded in achieving profound alterations in the nucleotide concentrations of cancer cells [22].

Gene context of Pyrazomycin

• DCC-mediated cyclization of 17, followed by debenzylation, gave pyrazofurin 3',5'-(cyclic)phosphate (21b) [15].
• In contrast, pyrazofurin and 6-azauridine, two nucleoside analogues that are assumed to interfere with OMP decarboxylase, another enzyme involved in the biosynthesis of pyrimidine ribonucleotides, potentiate the cytocidal activity of Ce-Cyd [23].
• These findings indicate that culture medium containing 2 microM pyrazofurin and 100 microM cytidine serves as a test medium for cytidine deaminase [24].
• Another resistant cell line that has a higher level of gene amplification when grown in the presence of pyrazofurin loses its elevated UMP synthase activity and amplified DNA sequences with growth in the absence of the drug [25].
• Pyrazofurin-resistant hepatoma cells deficient in adenosine kinase [26].

Analytical, diagnostic and therapeutic context of Pyrazomycin

• Amplification of the UMP synthase gene and enzyme overproduction in pyrazofurin-resistant rat hepatoma cells. Molecular cloning of a cDNA for UMP synthase [14].
• A number of nucleoside and nucleotide derivatives of 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin, 1) were prepared and tested for their antiviral and cytostatic activity in cell culture [15].
• Twenty-five patients with inoperable carcinoma and lymphoma were given pyrazofurin (pf) by iv bolus at a dose level ranging from 100 to 300 mg/m2 of estimated body surface area [27].

References