Cytotoxic mechanisms of glutamine antagonists in mouse L1210 leukemia

The glutamine antagonists, acivicin (NSC 163501), azaserine (NSC 742), and 6-diazo-5-oxo-L-norleucine (DON) (NSC 7365), are potent inhibitors of many glutamine-dependent amidotransferases in vitro. Experiments performed with mouse L1210 leukemia growing in culture show that each antagonist has diffe...

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Veröffentlicht in:The Journal of biological chemistry 1990-07, Vol.265 (19), p.11377-11381
Hauptverfasser: LYONS, S. D, SANT, M. E, CHRISTOPHERSON, R. I
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creator LYONS, S. D
SANT, M. E
CHRISTOPHERSON, R. I
description The glutamine antagonists, acivicin (NSC 163501), azaserine (NSC 742), and 6-diazo-5-oxo-L-norleucine (DON) (NSC 7365), are potent inhibitors of many glutamine-dependent amidotransferases in vitro. Experiments performed with mouse L1210 leukemia growing in culture show that each antagonist has different sites of inhibition in nucleotide biosynthesis. Acivicin is a potent inhibitor of CTP and GMP synthetases and partially inhibits N-formylglycineamidine ribotide (FGAM) synthetase of purine biosynthesis. DON inhibits FGAM synthetase, CTP synthetase, and glucosamine-6-phosphate isomerase. Azaserine inhibits FGAM synthetase and glucosamine-6-phosphate isomerase. Large accumulations of FGAR and its di- and triphosphate derivatives were observed for all three antagonists which could interfere with the biosynthesis of nucleic acids, providing another mechanism of cytotoxicity. Acivicin, azaserine, and DON are not potent inhibitors of carbamyl phosphate synthetase II (glutamine-hydrolyzing) and amidophosphoribosyltransferase in leukemia cells growing in culture although there are reports of such inhibitions in vitro. Blockade of de novo purine biosynthesis by these three antagonists results in a "complementary stimulation" of de novo pyrimidine biosynthesis.
doi_str_mv 10.1016/S0021-9258(19)38603-X
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D</creatorcontrib><creatorcontrib>SANT, M. E</creatorcontrib><creatorcontrib>CHRISTOPHERSON, R. I</creatorcontrib><title>Cytotoxic mechanisms of glutamine antagonists in mouse L1210 leukemia</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The glutamine antagonists, acivicin (NSC 163501), azaserine (NSC 742), and 6-diazo-5-oxo-L-norleucine (DON) (NSC 7365), are potent inhibitors of many glutamine-dependent amidotransferases in vitro. Experiments performed with mouse L1210 leukemia growing in culture show that each antagonist has different sites of inhibition in nucleotide biosynthesis. Acivicin is a potent inhibitor of CTP and GMP synthetases and partially inhibits N-formylglycineamidine ribotide (FGAM) synthetase of purine biosynthesis. DON inhibits FGAM synthetase, CTP synthetase, and glucosamine-6-phosphate isomerase. Azaserine inhibits FGAM synthetase and glucosamine-6-phosphate isomerase. Large accumulations of FGAR and its di- and triphosphate derivatives were observed for all three antagonists which could interfere with the biosynthesis of nucleic acids, providing another mechanism of cytotoxicity. Acivicin, azaserine, and DON are not potent inhibitors of carbamyl phosphate synthetase II (glutamine-hydrolyzing) and amidophosphoribosyltransferase in leukemia cells growing in culture although there are reports of such inhibitions in vitro. Blockade of de novo purine biosynthesis by these three antagonists results in a "complementary stimulation" of de novo pyrimidine biosynthesis.</description><subject>6-diazo-5-oxo-L-norleucine</subject><subject>Animals</subject><subject>azaserine</subject><subject>Azaserine - pharmacology</subject><subject>Azo Compounds - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Carbon-Nitrogen Ligases</subject><subject>Cell Line</subject><subject>Cell physiology</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Diazooxonorleucine - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>glutamine</subject><subject>Glutamine - antagonists &amp; inhibitors</subject><subject>Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - antagonists &amp; inhibitors</subject><subject>Isoxazoles - pharmacology</subject><subject>Leukemia L1210 - enzymology</subject><subject>Ligases - antagonists &amp; inhibitors</subject><subject>Mice</subject><subject>Molecular and cellular biology</subject><subject>Nucleotides - biosynthesis</subject><subject>Oxazoles - pharmacology</subject><subject>Responses to growth factors, tumor promotors, other factors</subject><subject>Spectrophotometry, Ultraviolet</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1990</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMtOwzAQRS0EKqXwCZWyAASLgN-xl6gqD6kSC0DqznLcSWuIE4gTQf-e9CGYxczi3pm5OgiNCb4hmMjbF4wpSTUV6oroa6YkZun8AA0JVixlgswP0fDPcoxOYnzHfXFNBmhAmVBcZkM0nazbuq1_vEsCuJWtfAwxqYtkWXatDb6CxFatXda90MbEV0mouwjJjFCCkxK6DwjenqKjwpYRzvZzhN7up6-Tx3T2_PA0uZuljmvWpjmFXGrKi1zhIgcHWmC56ANzYYu-55jbjGnLAcSioDmTFlwGhCqqtJKcjdDl7u5nU391EFsTfHRQlraCPpYhQmrMM9Ebxc7omjrGBgrz2fhgm7Uh2GzwmS0-s2FjiDZbfGbe7433D7o8wOJva8-r1y_2uo3OlkVjK-fj_3GdMYX5Juj5zrfyy9W3b8DkvnYrCIZKsXlICMsy9gsFZIOC</recordid><startdate>19900705</startdate><enddate>19900705</enddate><creator>LYONS, S. 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I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-b2eb6924fb80fbece9506d10845af084b04a739a4ee5df2b36aec7e1282898643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1990</creationdate><topic>6-diazo-5-oxo-L-norleucine</topic><topic>Animals</topic><topic>azaserine</topic><topic>Azaserine - pharmacology</topic><topic>Azo Compounds - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Carbon-Nitrogen Ligases</topic><topic>Cell Line</topic><topic>Cell physiology</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Diazooxonorleucine - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>glutamine</topic><topic>Glutamine - antagonists &amp; inhibitors</topic><topic>Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - antagonists &amp; inhibitors</topic><topic>Isoxazoles - pharmacology</topic><topic>Leukemia L1210 - enzymology</topic><topic>Ligases - antagonists &amp; inhibitors</topic><topic>Mice</topic><topic>Molecular and cellular biology</topic><topic>Nucleotides - biosynthesis</topic><topic>Oxazoles - pharmacology</topic><topic>Responses to growth factors, tumor promotors, other factors</topic><topic>Spectrophotometry, Ultraviolet</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LYONS, S. D</creatorcontrib><creatorcontrib>SANT, M. E</creatorcontrib><creatorcontrib>CHRISTOPHERSON, R. 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I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytotoxic mechanisms of glutamine antagonists in mouse L1210 leukemia</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1990-07-05</date><risdate>1990</risdate><volume>265</volume><issue>19</issue><spage>11377</spage><epage>11381</epage><pages>11377-11381</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><coden>JBCHA3</coden><abstract>The glutamine antagonists, acivicin (NSC 163501), azaserine (NSC 742), and 6-diazo-5-oxo-L-norleucine (DON) (NSC 7365), are potent inhibitors of many glutamine-dependent amidotransferases in vitro. Experiments performed with mouse L1210 leukemia growing in culture show that each antagonist has different sites of inhibition in nucleotide biosynthesis. Acivicin is a potent inhibitor of CTP and GMP synthetases and partially inhibits N-formylglycineamidine ribotide (FGAM) synthetase of purine biosynthesis. DON inhibits FGAM synthetase, CTP synthetase, and glucosamine-6-phosphate isomerase. Azaserine inhibits FGAM synthetase and glucosamine-6-phosphate isomerase. Large accumulations of FGAR and its di- and triphosphate derivatives were observed for all three antagonists which could interfere with the biosynthesis of nucleic acids, providing another mechanism of cytotoxicity. Acivicin, azaserine, and DON are not potent inhibitors of carbamyl phosphate synthetase II (glutamine-hydrolyzing) and amidophosphoribosyltransferase in leukemia cells growing in culture although there are reports of such inhibitions in vitro. Blockade of de novo purine biosynthesis by these three antagonists results in a "complementary stimulation" of de novo pyrimidine biosynthesis.</abstract><cop>Bethesda, MD</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>2358467</pmid><doi>10.1016/S0021-9258(19)38603-X</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record>
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subjects 6-diazo-5-oxo-L-norleucine
Animals
azaserine
Azaserine - pharmacology
Azo Compounds - pharmacology
Biological and medical sciences
Carbon-Nitrogen Ligases
Cell Line
Cell physiology
Chromatography, High Pressure Liquid
Diazooxonorleucine - pharmacology
Fundamental and applied biological sciences. Psychology
glutamine
Glutamine - antagonists & inhibitors
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - antagonists & inhibitors
Isoxazoles - pharmacology
Leukemia L1210 - enzymology
Ligases - antagonists & inhibitors
Mice
Molecular and cellular biology
Nucleotides - biosynthesis
Oxazoles - pharmacology
Responses to growth factors, tumor promotors, other factors
Spectrophotometry, Ultraviolet
title Cytotoxic mechanisms of glutamine antagonists in mouse L1210 leukemia
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