3-deazauridine and pyrazofurin

A variety of antiviral compounds were examined for their inhibitory effect on measles (SSPE) virus plaque formation in VERO cells. The following compounds inhibited SSPE virus (strain Niigata-1) replication at concentrations that were significantly lower than their minimum cytotoxic concentrations: neplanocin A, neplanocin C, carbocyclic 3-deazaadenosine, 9-(trans-2', trans-3'-dihydroxycyclopent-4'-enyl)adenine, 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine, (RS)-3-adenin-9-yl-2-hydroxypropanoic acid isobutyl ester, carbodine, cyclopentenyl cytosine, 3-deazaguanine, pyrazofurin, ribavirin and 6-azauridine. As the most selective inhibitors of SSPE virus replication emerged pyrazofurin, 3-deazaguanine, 6-azauridine and ribavirin. These compounds were further examined for their relative potency against a number of measles (SSPE) virus strains. Their order of (decreasing) potency was pyrazofurin greater than 6-azauridine approximately 3-deazaguanine greater than ribavirin. Amantadine, inosiplex and glycyrrhizin, that were also included in these assays, did not show appreciable activity against any of the measles (SSPE) virus strains.

Topics: 3-Deazauridine; Amides; Animals; Antiviral Agents; Azauridine; Measles virus; Nucleosides; Pyrazoles; Ribavirin; Ribonucleosides; Ribose; Vero Cells; Viral Plaque Assay; Virus Replication

Pyrazofurin (NSC 143095) as the monophosphate derivative is a potent inhibitor of orotidine 5'-monophosphate (OMP) decarboxylase of the pyrimidine pathway and has been proposed to inhibit 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (EC 2.1.2.3) of the purine pathway (J. F. Worzalla, and M. J. Sweeney, Pyrazofurin inhibition of purine biosynthesis via 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate formyltransferase. Cancer Res., 40: 1482-1485, 1980). Measurement of levels of pyrimidine and purine intermediates in cultured mouse L1210 leukemia cells has shown that 25 microM pyrazofurin induces an 8-fold accumulation of OMP and large accumulations of intermediates proximal to the blockade with abrupt decreases in uridine and cytidine nucleotides. Considerable increases in the cellular concentrations of N-succino-AICAR (SAICAR), AICAR, 5-formamidoimidazole-4-carboxamide ribotide (FAICAR), IMP, XMP, and GMP at later times indicate that AICAR transformylase is not significantly inhibited in cultured cells; rather the purine pathway and the GMP branch are stimulated. However, addition of 25 microM 3-deazauridine (NSC 126849) to leukemia cells did result in inhibition of AICAR transformylase: AICAR and SAICAR accumulated, IMP disappeared and there was a large accumulation of guanosine nucleotides. Blockade of pyrimidine biosynthesis by derivatives of pyrazofurin or 3-deazauridine spares 5-phosphoribosyl-1-pyrophosphate and L-glutamine, elevated concentrations of which may stimulate initial reactions of purine biosynthesis and the reaction XMP----GMP.

Topics: 3-Deazauridine; Acyltransferases; Amides; Animals; Antibiotics, Antineoplastic; Bicarbonates; Hydroxymethyl and Formyl Transferases; Leukemia L1210; Mice; Orotidine-5'-Phosphate Decarboxylase; Phosphoribosylaminoimidazolecarboxamide Formyltransferase; Purines; Pyrazoles; Pyrimidines; Ribonucleosides; Ribose; Tumor Cells, Cultured; Uridine

The effect of high concentrations of exogenous dCyd on the growth inhibitory properties of several inhibitors of de novo pyrimidine biosynthesis (dThd, 3-DAU, PALA, PF) was examined in three cultured human leukemic cell lines (HL-60, K-562, KG-1), and a dCyd kinase-deficient, Ara-C-resistant variant (HL-60/Ara-C). In the presence of dCyd concentrations (10(-3) M), far exceeding normal human plasma levels (0.5 to 4.0 X 10(6) M), substantial but partial reversal of pyrimidine antagonist-mediated growth inhibition and restoration of intracellular dCTP levels was noted in all cell types except HL-60/Ara-C. When high concentrations of dCyd (10(-3) M) were combined with low levels of uridine or cytidine (10(-5) M), full restoration of growth was observed in sensitive cell lines. When exposed to supraphysiologic concentrations of dCyd, HL-60/Ara-C cells were more sensitive to the growth inhibitory effects of pyrimidine antagonists than parent HL-60 cells; this phenomenon was maximal at 10(-4) M dCyd and was not observed in the presence of dCyd concentrations of 10(-6) M or lower. These studies suggest that in the presence of low concentrations of uridine or cytidine, perturbations in intracellular dCTP pools may play a critical role in determining the in vitro antiproliferative response of human leukemic myeloid cells to diverse inhibitors of de novo pyrimidine biosynthesis. They also raise the possibility that modulation of exogenous dCyd concentrations may improve the therapeutic efficacy of pyrimidine antagonists toward certain salvage pathway-deficient, drug-resistant leukemic cells.

Topics: 3-Deazauridine; Amides; Aspartic Acid; Cell Division; Cell Line; Deoxycytidine; Deoxycytidine Kinase; Drug Interactions; Humans; Leukemia, Experimental; Phosphonoacetic Acid; Pyrazoles; Pyrimidines; Ribonucleosides; Ribose; Thymidine