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At least 19 recordsLinked to original sources
PubMed1978

Tubercidin metabolism in mouse L5178y cells in vivo and in vitro.

Tubercidin (7-deazaadenosine) is a strong inhibitor of cell proliferation in mouse L5178y cells. Radioactive tubercidin is incorporated into DNA and RNA. Poly(A)-containing RNA shows the highest specific radioactivity. The amount of low molecular weight 4S and 5S RNA is diminished to some extent under the influence of the compound. Tubercidin triphosphate is a potent inhibitor of DNA-dependent DNA polymerases alpha and beta, and the DNA-dependent RNA polymerases I, II, and III, although the efficiency of its incorporation is lower than of dATP and ATP. Tubercidin triphosphate also seems to be a good substrate for the Mg2+-dependent poly(A) polymerase.

Animals↗
PubMed1979

High frequency of mutation to tubercidin resistance in CHO cells.

The acquisition of high-level resistance to tubercidin (an adenosine analog) in CHO cells occurs in a single step at high frequency (10(-3) to 10(-4)) without mutagenesis. Analysis of a large number of independent mutants by a fluctuation test (Luria and Delbruk, 1943) indicates that they arise independently of the selection medium and all fall into the same complementation group. All mutants tested lack detectable adenosine kinase activity. An analysis of hybrids between mutant and wild-type cells indicates that resistance to tubercidin is a recessive marker which segregates as would be expected if it were a haploid locus in the parental CHO cell. Resistance to tubercidin is not linked to the X chromosome in CHO cells and appears to occur at much lower frequency in primary Chinese hamster cells and other cultured cell lines.

Animals↗
PubMed1975

A study on the reactions of tubercidin triphosphate with myosin and actomyosin.

The triphosphate ester of tubercidin (tubercidin triphosphate, TuTP) was synthesized. This is an analog of ATP in which a CH group replaces the N-7 of the adenine ring. The rate of TuTP hydrolysis by myosin in the presence of Mg2+ was the same as that of ATP in the 10(-7)-10(-3) M range, whereas the increment in the optical density of myosin ihe 290mmu region caused by TuTP was twice that caused by ATP. TuTP is hydrolyzed by actomyosin faster than ATP, the value of Vmax being about 4 times larger while the Km values were of the same order of magnitude. The rate of superprecipitation induced by TuTP was 50% of that caused by ATP at nucleotide concentrations of 3-60 muM. A similar difference was observed with respect to the rate of tension development by glycerol-extracted rabbit psoas fibers upon addition of these two substances. Substitution of ADP by tubercidin diphosphate (TuDP) in F-actin did not affect the rate of superprecipitation or enzymic activity of actomyosin.

Actomyosin↗
PubMed1978

Genetic and biochemical studies with the adenosine analogs toyocamycin and tubercidin: mutation at the adenosine kinase locus in Chinese hamster cells.

The pyrrolopyrimidine nucleosides toyocamycin and tubercidin show several unique features of growth inhibition in Chinese hamster ovary (CHO) cells. Stable mutants which are more than 600-fold resistant to these drugs are obtained in CHO cells at a strikingly high frequency of approximately 10(-3), in the absence of mutagenesis. The mutants resistant to toyocamycin (Toyr) and tubercidin (Tubr) exhibit similar cross-resistance patterns to the two selective drugs as well as to adenosine and 6-methyl mercaptopurine riboside, indicating that the same lesion is probably involved in all cases. The mutants examined were found to be deficient in the enzyme adenosine kinase (AK), indicating that the phosphorylation of these analogs is an essential first step in their toxic action. The above mutants (AK-) behaved recessively in cell hybrids, and segregation studies indicate that the AK locus is not linked to the X chromosome. The frequencies of similar Toyr mutants in other Chinese hamster lines, e.g., V79, CHW, M3-1, GM7, and CHO-K1, varied from similar to more than three logs less than that observed for CHO cells, indicating that various cell lines probably differ in the number of functional gene copies for this locus.

Adenosine Kinase↗
PubMed1979

5-FU versus combination therapy with tubercidin, streptozotocin, and 5-FU in the treatment of pancreatic carcinomas: COG protocol 7230.

From May 1972 until May 1976, 105 patients were entered on Central Oncology Group protocol 7230 to compare the combination of streptozotocin, tubercidin, and 5-fluorouracil (5-FU) versus 5-FU alone in the treatment of adenocarcinoma and islet cell carcinoma of the pancreas. Twenty-nine were not evaluable. Thirty-six evaluable cases received 5-FU, and 40 received the combination, with no significant difference in time to progression or survival. Toxicity in the two regimens was somewhat different but was essentially similar in magnitude. Results indicate no benefit in the treatment of adenocarcinoma of the pancreas with the three-drug combination over 5-FU alone. All of the islet cell tumor patients benefited from the combination by response or arrest of progression of disease. Further study should be directed toward the use of this combination in the treatment of functioning and non-functioning islet cell tumors of the pancreas.

Adenocarcinoma↗
PubMed1975

Long-term efficacy of tubercidin against schistosomiasis japonica and mansoni in primates.

Schistosomiasis japonica in capuchin msnkeys (Cebus apella) and schistosomiasis mansoni in baboons (Papio cyanocephalus and P. hamadryas) were completely arrested for 6 months in every infected primate receiving a single treatment with tubercidin (Tu), administered after prior absorption into 20% of their red cells. It is very likely that a single treatment with Tu sequestered in only 15% of the hosts' red cells would also be 100% effective for prolonged periods of time, but that with lower doses some relapses would be expected. Babbons with patent Schistosoma mansoni infections were rechallenged with S. mansoni cercariae 4 months after treatment with Tu. Although Tu eliminated almost all the sexually mature female worms from the primary infection but spared most of the males for continuing sojourn within their hosts, the baboons retained their full susceptibility to reinfection, as indicated by worm burdens and fecal egg excretion. However, the granulomatous reaction in the rechallenged Tu-treated baboons to new masses of eggs trapped in their livers appeared to be less intense than was seen in animals with primary infections.

Animals↗
PubMed1976

Synthesis and biological activity of pyrazolo[3,4,-d]pyrimidine nucleosides and nucleotides related to tubercidin, toyocamycin, and sangivamycin.

The 6-aza analogues of toyocamycin and sangivamycin were prepared as potential cytotoxic agents. The toyocamycin analogue (4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-carbonitrile) could not be obtained directly from its O-acetylated precursor but was accessible via 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-thiocarboxamide. The identity of the nitrile was verified by its ultraviolet, infrared, and mass spectra, and by its conversion to the corresponding 3-carboxamide and thiocarboxamide when treated with water or hydrogen sulfide, respectively. Bioassay of the synthetic compounds in comparison with 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6-azatubercidin) and 4-amino-2-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine revealed that the 3-thiocarboxamido derivative was more cytotoxic to the growth of mouse fibroblasts than 6-azatubercidin, effecting killing of 3T6 cells at less than or equal to 1 mug/ml. 4-Amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (but not its 2-ribofuranosyl isomer) was shown to act as a substrate for adenosine deaminase from calf intestinal mucosa with an apparent Km of 125 (vs. 20 for adenosine) and the corresponding 5'-diphosphate of 6-azatubercidin was polymerized by polynucleotide phosphorylase (Micrococcus luteus) in the presence of Mn2+ to afford a homopolymer and copolymers with adenosine. The copolymers directed the binding of [3H]lysyl-tRNA to the A-site of ribosomes from Escherichia coli, but could not be used for the synthesis of polylsine in a cellfree system. The copolymer consiting of adenosine and 6-azatubercidin in a 2:1 ratio was found to form a 1:1 complex with poly(uridylic acid) at 4degreesC.

Antibiotics, Antineoplastic↗
PubMed1979

Relationships among purine nucleoside metabolism, adenosine triphosphate catabolism, and glycolysis in human erythrocytes.

In human erythrocytes incubated with both naturally occurring purine nucleosides and with a variety of purine nucleoside analogs, ATP catabolism was accelerated and lactate accumulation was increased. Tubercidin was a particularly potent inducer of ATP catabolism. In cells incubated with tubercidin, the major route of adenylate metabolism was deamination, whereas in cells incubated with deoxyglucose, the major pathway was dephosphorylation.

Adenosine Deaminase Inhibitors↗
PubMed1977

Isolation of variants in phagocytosis of a macrophage-like continuous cell line.

We have isolated cloned variants in phagocytosis from a cloned continuous murine macrophage-like cell line, J 774.2. A selection procedure against Fc receptor-mediated phagocytosis was devised using IgG-coated SRBC containing a toxic drug, tubercidin, as the lethal agent. A series of variant clones deficient in Fc receptor-mediated phagocytosis were isolated. Such variants occurred at low frequency (approximately 6 X 10(-5)), were stable, and appeared to possess Fc receptors. The degree to which they were defective in phagocytosis of IgG-coated SRBC varied from clone to clone, yet all clones, were able to phagocytize latex particles. The phagocytic defect in some variants could be corrected by the addition of 8 Br-cAMP, in others, the drug was without effect. It is likely, therefore, that different variants are defective in several distinct steps critical to Fc receptor-mediated phagocytosis.

Binding Sites↗
PubMed1976

Observations on the postoperative tumor growth behavior of certain islet cell tumors.

Over a period of 21 years 39 patients with gastrinoma were surgically treated. Thirty-three patients had total gastrectomy with two postoperative deaths, and 6 patients had a lesser procedure. The postoperative fasting gastrin levels remained elevated and did not always indicate the extent of tumor involvement. Further mobilization of tumor gastrin by provocative infusion of calcium gluceptate, 15 mg/kg of body weight, should be carried out routinely. A hepatic angiogram should be considered when the gastrin levels exceed 1,000 picograms per ml. Chemotherapy consisting of Tubercidin, Streptozotocin and 5-Fluorouracil was given to 5 patients with extensive gastrinoma. All patients felt better and gained from three to 35 pounds in weight. Since 60% of the patients died or have definite evidence of tumor activity it is assumed that the tumor growth was not inhibited and that it is malignant. Approximately 40% of the patients seem to do well despite modest elevations in gastrin levels suggesting that the retained tumor could be considered benign.

Adenoma, Islet Cell↗
PubMed1978

IV. Synthesis and assay of analogs of adenosine 3',5'-diphosphate as inhibitors of bovine adrenal estrogen sulfotranferase.

Analogs of adenosine 3',5'-diphosphate are described which aid in the characterization of the inhibition of estrone sulfurylation by 3'-phosphoadenosine 5'-phosphosulfate as mediated by bovine adrenal estrogen sulfotransferase (3'-5'-phosphosulfate:estrone 3-sulphotransferase, EC 2.8.2.4). The facile conversion of ribonucleosides to 2',3'-cyclic phosphate 5'-phosphate in neat pyrophosphoryl chloride is utilized to provide a reliable route to the requisite intermediates for enzymatic regiospecific conversion to ribonucleoside 3',5'- and 2',5'-diphosphates. The importance of the 3'-phosphate ester to inhibition of estrone sulfurylation is confirmed by Ki measurements. Replacement of the 6-amino group by hydrogen or oxygen leads to considerable loss in affinity for the enzyme as does also dimethylation of the exocylic amino group. Alterations in the pyrimidine ring are not well tolerated by the sulfotransferase but modifications in the imidazole ring as in tubercidin (7 -deazaadenosine) and 8-bromoadenosine 3',5'-diphosphate lead to an enhanced affinity. The latter findings are discussed in terms of an hypothesis of stacking of the aromatic ring of the estrogen substrate and the purine moiety and its analogs.

Adenine Nucleotides↗
PubMed1975

Cyclic adenosine monophosphate receptor: effect of cyclic AMP analogues on DNA binding and proteolytic inactivation.

The cyclic AMP receptor protein of Escherichia coli in the presence of cyclic AMP undergoes a conformational change resulting in an increased affinity for DNA and an increased susceptibility to attack by proteolytic enzymes resulting in loss of DNA binding capacity. Of several cyclic nucleotides tested only cyclic AMP and cyclic tubercidin monophosphate are able to effect the conformational transition in cyclic AMP receptor protein, prerequisite to proteolytic inactivation or DNA binding. Other analogues such as cyclic GMP or cyclic IMP which are competitive inhibitors of cyclic AMP do not support DNA binding or proteolytic inactivation.

Bacterial Proteins↗
PubMed1979

Cytoplasmic location of undermethylated messenger RNA in Novikoff cells.

Novikoff cells in culture were labeled with L-[methyl-3H]methionine and [U-14C]uridine in the presence of (a) TubHcy2, (b) AdoHcy, (c) homocysteine, (d) tubercidin, or (e) without any additions. Only in cultures labeled in the presence of TubHcy were undermethylated cap structures observed to represent a significant portion of [3H]methyl radioactivity. Novikoff cells in culture were then simultaneously labeled with L-[methyl-3H]methionine and [32P]orthophosphate in the presence or absence of TubHcy. Total cytoplasmic, polysomal and monosomal poly(A)-containing RNAs were analyzed. Both monosomal and polysomal mRNA fractions from TubHcy-treated cells contain partially methylated cap structures, suggesting that 2'-O-methylation of the nucleoside adjacent to the pyrophosphate linkage in caps is not required for transport, ribosomal binding or translation. Comparison of nuclear and cytoplasmic cap structures from normal and inhibited cultures indicate that an altered mRNA population is generated in the presence of TubHcy.

Animals↗
PubMed1977

Enhancement of the biological activity of adenosine analogs by the adenosine deaminase inhibitor 2'-deoxycoformycin.

The potent adenosine deaminase inhibitor 2'-deoxycoformycin ((R)-3-(2-deoxy-beta-D-erythropentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol) inhibits the enzymic inactivation and potentiates the cytotoxic activity of a variety of adenosine analogs in the P388 murine leukemia cell culture system. The activity of all seven adenosine analogs examined was enhanced by 2'-deoxycoformycin with the exception of tubercidin (7-deaza-adenosine) which is not a substrate for the deaminase. In vivo, 2'-deoxy-coformycin potentiated the antineoplastic activity of 9-beta-D-xylofuranosyladenine in mice with P388 murine leukemia.

Adenosine↗
PubMed1975

A purine nucleoside hydrolase from Trypanosoma gambiense, purification and properties.

A purine nucleoside hydrolase from Trypanosoma gambiense was purified 160-fold. Preferred substrates of the reaction were adenosine, inosine and guanosine with a maximum of activity at pH 5.4. Competitive inhibitors of the adenosine hydrolysis were dimethylallyl adenosine, 6-methylmercaptopurine riboside, tubercidin, formycin B, 6-mercaptopurine riboside and deoxyadenosine. A metabolic scheme of adenosine nomophosphate salvage synthesis is discussed.

Adenine Phosphoribosyltransferase↗