Barbara A. Booth

Iowa Diabetes and Endocrinology Research Center

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Alan C. Sartorelli

Yale University

Robert S. Bar

Iowa Diabetes and Endocrinology Research Center

Brian L. Dake

University of Iowa

Krishna C. Agrawal

Eindhoven University of Technology

M. Boes

Children's Minnesota

Mary Boes

University of Minnesota System

E. Colleen Moore

Merck & Co., Inc., Rahway, NJ, USA (United States)

Joseph R. Bertino

Rutgers Cancer Institute of New Jersey

Kriti Agrawal

Yale University

A.E. Colás

Hospital Universitario Puerta de Hierro Majadahonda

Cooperative Institutions

University of Iowa

Iowa Diabetes and Endocrinology Research Center

Yale University

United States Department of Veterans Affairs

University of North Carolina at Chapel Hill

Merck & Co., Inc., Rahway, NJ, USA (United States)

University of Florida

Stanford University

University of Wisconsin–Madison

Oregon Health & Science University

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Inhibition of the Synthesis of Thymine Nucleotides by Azaserine

Molecular Pharmacology (1967)

Alan C. Sartorelli Barbara A. Booth

The synthesis of purine nucleotides de novo in sarcoma 180 ascites cells propagated in mice was essentially completely inhibited for a prolonged period of time by azaserine ( O -diazoacetyl-L-serine); this metabolic blockade resulted in a 60% decrease in the amount of adenine nucleotides in time cells. Concurrently, in the antibiotic-treated cells, the incorporation of thymidine-3H, formate-14C and deoxycytidine-3H into the thymine of DNA was markedly depressed, while the utilization of orotic acid-14C and leucine-14C for the formation of RNA and proteins, respectively, was unaffected. Azaserine did not decrease the rate of incorporation of adenine-14C into the purine nucleotides of DNA and RNA, suggesting that the polymerization processes per se were not altered by the drug. The inhibition of the incorporation of labeled precursors into the thymine of DNA in azaserine-treated cells was accounted for by a pronounced depression in the levels of thymidine kinase (ATP:thymidine 5'-phosphotransferase, EC [2.7.1.21][1]) and thymidine monophosphate kinase (ATP:thymidine monophosphate phosphotransferase, EC [2.7.4.9][1]). The availability to the cells of a supply of preformed adenine restored both the azaserinedepleted pool of adenine nucleotides and the activities of the thymine nucleotide-synthesizing enzymes; in this capacity, hypoxanthine was only slightly effective, while guanosine and azapurines were ineffective in reversing the azaserine-induced metabolic lesions. The results suggested a possible role for adenine nucleotides in regulating the activities of thymidine kinase and thymidine monophosphate kinase in intact cells. ACKNOWLEDGMENTS This investigation was supported by USPHS Research Giant CA-02817 from the National Cancer Institute. The authors wish to thank Mrs. Theresa Cheng, Miss Florence C. Dunmore, Miss Sheila J. Feld, and Miss Andrea F. Gorske for excellent technical assistance. [1]: pending:yes

Azaserine

Thymidine

Thymine

Thymidine kinase

Uracil

Nucleotide salvage

Ribonucleotide

10.1016/s0026-895x(25)14729-9

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Citations (7)

Purine synthesis in sarcoma 180 and hetapoma 134 ascites cells treated with 6-chloropurine or azaserine. Abstr.

Alan C. Sartorelli Barbara A. Booth

Azaserine

Purine metabolism

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COMPARATIVE STUDIES ON THE IN VIVO ACTION OF 6-CHLOROPURINE, 6-CHLOROPURINE RIBONUCLEOSIDE, AND 6-CHLORO-9-ETHYLPURINE ON SARCOMA 180 ASCITES CELLS

Journal of Pharmacology and Experimental Therapeutics (1961)

Alan C. Sartorelli Barbara A. Booth

6-Chloropurine and 6-chloropurine ribonucleoside both inhibited the incorporation of glycine-2-C14 into polynucleotide guanine without decreasing the rate of incorporation into adenine compounds of sarcoma 180 ascites cells. On a molar basis, the ribonucleoside was more active. Treatment with either drug caused a similar increase in the conversion of adenine-8-C14 or guanine-8-C14 to polynucleotide guanine. 6-Chloro-9-ethylpurine was relatively inactive; neither inhibition of labeled glycine into guanine nucleotides nor stimulation of preformed purine utilization for polynucleotide synthesis was observed after treatment with this agent. 6-Chloropurine ribonucleoside and 6-chloro-9-ethylpurine were ineffective inhibitors of the growth of sarcoma 180. These results are similar to past observations obtained with chloropurine. 6-Chloro-9-ethylpurine was relatively inactive in its ability to enhance the carcinostatic properties of azaserine, a previously demonstrated property of chloropurine. Chloropurine ribonucleoside reversed the carcinostatic action of azaserine and markedly decreased the effectiveness of a combination of chloropurine and azaserine. The results of these studies are discussed in relation to the biochemical mechanisms responsible for the drug synergy exhibited by combinations of chloropurine and azaserine.

Azaserine

Ribonucleoside

Polynucleotide

10.1016/s0022-3565(25)26139-0

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Citations (4)

IGFBP-3 binding to endothelial cells inhibits plasmin and thrombin proteolysis

AJP Endocrinology and Metabolism (2002)

Barbara A. Booth M. Boes Brian L. Dake Kevin L. Knudtson Robert S. Bar

Insulin-like growth factor-binding protein (IGFBP)-3 contains a highly basic COOH-terminal heparin-binding region, the P3 region, which is thought to be important in the binding of IGFBP-3 to endothelial cells. IGFBP-3 and IGFBP-4, and their chimeras IGFBP-3 4 and IGFBP-4 3 , were treated with plasmin and with thrombin, proteases known to cleave IGFBP-3. IGFBP-3 was highly susceptible to plasmin, whereas IGFBP-4 was less so. Substitution of the P3 region for the P4 region in IGFBP-4 (IGFBP-4 3 ) increased the ability of the protease to digest IGFBP-4 3 ; substitution of the P4 region for the P3 region in IGFBP-3 (IGFBP-3 4 ) decreased the digestion of IGFBP-3 4 . When 125 I-labeled IGFBP-3 or 125 I-IGFBP-4 3 was first bound to vascular endothelial cells, subsequent proteolysis by either plasmin or thrombin was substantially inhibited. Proteolysis of 125 I-IGFBP-3 4 was not inhibited in the presence of endothelial cells. The P3 peptide was cleaved by plasmin but not by thrombin. We conclude that the P3 region is central to proteolysis of IGFBP-3 by plasmin and thrombin, processes which were inhibited by association of IGFBP-3 with endothelial cells.

Proteolysis

10.1152/ajpendo.2002.282.1.e52

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Citations (13)

Book Reviews

Gynecologic and Obstetric Investigation (1975)

Leon Milewich Celso E. Gómez-Sánchez James D. Madden Paul C. MacDonald R.M. Abrams

10.1159/000301527

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Citations (0)

Author Index

Journal of Biological Chemistry (1964)

Glutathione Gebicei F. Robert Hunter J Deter- Mination Counter Abe Jacob Berger

10.1016/s0021-9258(18)51685-9

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Citations (1)

Complex formation with DNA and inhibition of nucleic acid synthesis by methylglyoxal bis(guanylhydrazone)

Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis (1965)

Alan C. Sartorelli A.T. Iannotti Barbara A. Booth F.H. Schneider Joseph R. Bertino

Divalent

DNA polymerase I

10.1016/0005-2787(65)90550-2

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Citations (22)

Enzymic oxidation of methotrexate and aminopterin

Life Sciences (1964)

David G. Johns A.T. Iannotti Alan C. Sartorelli Barbara A. Booth Joseph R. Bertino

Aminopterin

10.1016/0024-3205(64)90078-5

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Citations (26)

Metabolic Effects of Copper in Intact Cells: Comparative Activity of Cupric Chloride and the Cupric Chelate of Kethoxal Bis(thiosemicarbazone)

Molecular Pharmacology (1967)

Barbara A. Booth Alan C. Sartorelli

The exposure of sarcoma 180 ascites cells to the cupric chelate [Cu(II)KTS] of kethoxal bis(thiosemicarbazone) (KTS) resulted in the death of a large proportion of the cell population; both the ligand portion of the molecule, KTS, and cupric chloride were less toxic. Cells isolated from mice treated with Cu(II)KTS contained considerably greater amounts of copper than did those cells exposed to the same number of gram-atoms of copper presented as either copper chloride or copper stearate. The results suggested that the relatively lipidsoluble chelate-form of copper was more readily assimilated. Dissociation of Cu(II)KTS occurred within neoplastic cells, and this resulted in a relatively rapid loss from the cells of the ligand portion, KTS. In contrast, the copper derived from Cu(II)KTS persisted for a much longer period of time. The relationship of nucleic acid and protein synthesis to the phenomenon of cell death induced by these agents was assessed by measuring the effects of the compounds on these metabolic processes. The formation of DNA was more sensitive to the inhibitory action of Cu(II)KTS, CuCl 2 , and KTS, than were either the syntheses of RNA or protein. In agreement with the cellular toxicity, Cu(II)KTS caused more pronounced depression of the incorporation of isotopic precursors into DNA than did either CuCl 2 or KTS. The copper present in cells treated with Cu(II)KTS induced at least three metabolic blocks on the pathways of DNA biosynthesis. The most sensitive site was measured by the incorporation of thymidine- 3 H into DNA and presumably was the result of the loss of activity of thymidine kinase. The findings obtained using a variety of isotopic precursors of DNA as biochemical probes suggested that the intracellular localization of copper derived from Cu(II)KTS differed from that of CuCl 2 .

Semicarbazone

Copper chloride

Copper toxicity

10.1016/s0026-895x(25)14796-2

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Citations (29)

Insulin-like growth factor binding protein production by bovine and human vascular smooth muscle cells: production of insulin-like growth factor binding protein-6 by human smooth muscle.

Endocrinology (1996)

M. Boes Barbara A. Booth Brian L. Dake David J. Moser Robert S. Bar

Insulin-like growth factor binding protein (IGFBP) secretory profiles were determined for vascular smooth muscle cells (VSMC) derived from bovine aorta and human aorta, pulmonary artery, and coronary artery. The bovine cells produced IGFBP-4, IGFBP-3, and an IGFBP-3 protease. IGF-I stimulated messenger RNA (mRNA) and media levels of IGFBP-3. The human cells produced IGFBP-3, IGFBP-4, and IGFBP-3 and IGFBP-4 proteases. The three human cells also produced a 30K IGFBP, shown to be IGFBP-6, based on increased affinity for IGF-II vs. IGF-I, size decrease when treated with O-glycanase, but not N-glycanase, reactivity with IGFBP-6 antiserum, presence of a 1.3-kilobase pair mRNA that hybridized to IGFBP-6 specific complementary DNA, and N-terminal amino acid sequence corresponding to IGFBP-6. In the human cells, IGF-I increased media levels of IGFBP-3 through stimulation of IGFBP-3 mRNA and dissociation of cell bound IGFBP-3, and decreased IGFBP-4 via potentiation of IGFBP-4 proteolysis. Neither the bovine nor the human aorta VSMC produced sufficient IGFBP-2 or IGFBP-2 mRNA to be detected by ligand blot and Northern analysis, as previously reported for porcine and rat aorta smooth muscle cells. The variable expression of IGFBPs and IGFBP proteases by VSMC are likely to contribute to differential vascular reactivity to the IGFs in larger arterial blood vessels.

10.1210/endo.137.12.8940357

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Citations (18)