Selective inhibition of pyrimidine biosynthesis and effect on proliferative growth of colonic cancer cells
A highly selective inhibition of de novo pyrimidine synthesis in the intact cell has been demonstrated by the action of N-(phosphonacetyl)-L-aspartate (PALA), a transition-state analog inhibitor of the reaction catalyzed by asparate transcarbamylase. The effect of pyrimidine deprivation induced by t...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1977-09, Vol.37 (9), p.3080-3087 |
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| container_issue | 9 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Tsuboi, K K Edmunds, N H Kwong, L K |
| description | A highly selective inhibition of de novo pyrimidine synthesis in the intact cell has been demonstrated by the action of N-(phosphonacetyl)-L-aspartate (PALA), a transition-state analog inhibitor of the reaction catalyzed by asparate transcarbamylase. The effect of pyrimidine deprivation induced by this agent on the viability and survival of human normal (WI-38) and colonic cancer cells (HT-29) was examined. The PALA-treated, pyrimidine-deprived cells failed to grow but demonstrated a normal rate of glucose utilization with impaired glycogen synthesis. Pyrimidine deprivation and lack of cell growth were maintained long after PALA removal. Growth inhibition of HT-29 cells by PALA was found to reflect an apparent steady state between newly formed and dying cells induced by limited pyrimidine availability. The highly selective nature of PALA action was confirmed by the ability of an exogenous source of pyrimidine to restore the normal growth pattern of the cell. Significant antitumor activity of PALA was found against a transplantable colonic tumor (line 26) carried in mice. |
| format | Article |
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The effect of pyrimidine deprivation induced by this agent on the viability and survival of human normal (WI-38) and colonic cancer cells (HT-29) was examined. The PALA-treated, pyrimidine-deprived cells failed to grow but demonstrated a normal rate of glucose utilization with impaired glycogen synthesis. Pyrimidine deprivation and lack of cell growth were maintained long after PALA removal. Growth inhibition of HT-29 cells by PALA was found to reflect an apparent steady state between newly formed and dying cells induced by limited pyrimidine availability. The highly selective nature of PALA action was confirmed by the ability of an exogenous source of pyrimidine to restore the normal growth pattern of the cell. Significant antitumor activity of PALA was found against a transplantable colonic tumor (line 26) carried in mice.</description><identifier>ISSN: 0008-5472</identifier><identifier>PMID: 884665</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Aspartic Acid - administration & dosage ; Aspartic Acid - analogs & derivatives ; Aspartic Acid - pharmacology ; Cell Division - drug effects ; Cells, Cultured ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; DNA, Neoplasm - biosynthesis ; Humans ; Kinetics ; Mice ; Mice, Inbred BALB C ; Neoplasm Transplantation ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - metabolism ; Neoplasms, Experimental - pathology ; Organophosphorus Compounds - administration & dosage ; Organophosphorus Compounds - pharmacology ; Pyrimidines - biosynthesis ; Pyrimidines - pharmacology ; Transplantation, Isogeneic ; Uridine - pharmacology</subject><ispartof>Cancer research (Chicago, Ill.), 1977-09, Vol.37 (9), p.3080-3087</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/884665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tsuboi, K K</creatorcontrib><creatorcontrib>Edmunds, N H</creatorcontrib><creatorcontrib>Kwong, L K</creatorcontrib><title>Selective inhibition of pyrimidine biosynthesis and effect on proliferative growth of colonic cancer cells</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>A highly selective inhibition of de novo pyrimidine synthesis in the intact cell has been demonstrated by the action of N-(phosphonacetyl)-L-aspartate (PALA), a transition-state analog inhibitor of the reaction catalyzed by asparate transcarbamylase. The effect of pyrimidine deprivation induced by this agent on the viability and survival of human normal (WI-38) and colonic cancer cells (HT-29) was examined. The PALA-treated, pyrimidine-deprived cells failed to grow but demonstrated a normal rate of glucose utilization with impaired glycogen synthesis. Pyrimidine deprivation and lack of cell growth were maintained long after PALA removal. Growth inhibition of HT-29 cells by PALA was found to reflect an apparent steady state between newly formed and dying cells induced by limited pyrimidine availability. The highly selective nature of PALA action was confirmed by the ability of an exogenous source of pyrimidine to restore the normal growth pattern of the cell. Significant antitumor activity of PALA was found against a transplantable colonic tumor (line 26) carried in mice.</description><subject>Animals</subject><subject>Aspartic Acid - administration & dosage</subject><subject>Aspartic Acid - analogs & derivatives</subject><subject>Aspartic Acid - pharmacology</subject><subject>Cell Division - drug effects</subject><subject>Cells, Cultured</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>DNA, Neoplasm - biosynthesis</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Neoplasm Transplantation</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - metabolism</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Organophosphorus Compounds - administration & dosage</subject><subject>Organophosphorus Compounds - pharmacology</subject><subject>Pyrimidines - biosynthesis</subject><subject>Pyrimidines - pharmacology</subject><subject>Transplantation, Isogeneic</subject><subject>Uridine - pharmacology</subject><issn>0008-5472</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1977</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNotkEtPwzAQhH3gVQr_gINP3CI5cRw7R1TxkipxAM6RHxuyVWIXOwHl35PSnkYrfTOa2TOyYoypTJSyuCLXKe2WU-RMXJILpcqqEiuye4ce7Ig_QNF3aHDE4Glo6X6OOKBDD9RgSLMfO0iYqPaOQtsuHrqA-xh6bCHq_4SvGH7H7uC2oQ8eLbXaW4jUQt-nG3Le6j7B7UnX5PPp8WPzkm3fnl83D9usK7gas7x0TuUOODBpHQgnKmC1zVtZqqqoNWhpamuMcLJSooQcWGGFrCUUzNaV5Wtyf8xdyn1PkMZmwHRooD2EKTWK10LmvFjAuxM4mQFcs18W6zg3x9_wP6LtYb8</recordid><startdate>197709</startdate><enddate>197709</enddate><creator>Tsuboi, K K</creator><creator>Edmunds, N H</creator><creator>Kwong, L K</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>197709</creationdate><title>Selective inhibition of pyrimidine biosynthesis and effect on proliferative growth of colonic cancer cells</title><author>Tsuboi, K K ; Edmunds, N H ; Kwong, L K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h238t-14dd81de3e07cde5d56e09c1f748629aea7b9cbb5d76854e1e02c5797e20c96c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1977</creationdate><topic>Animals</topic><topic>Aspartic Acid - administration & dosage</topic><topic>Aspartic Acid - analogs & derivatives</topic><topic>Aspartic Acid - pharmacology</topic><topic>Cell Division - drug effects</topic><topic>Cells, Cultured</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - pathology</topic><topic>DNA, Neoplasm - biosynthesis</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Neoplasm Transplantation</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - metabolism</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Organophosphorus Compounds - administration & dosage</topic><topic>Organophosphorus Compounds - pharmacology</topic><topic>Pyrimidines - biosynthesis</topic><topic>Pyrimidines - pharmacology</topic><topic>Transplantation, Isogeneic</topic><topic>Uridine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tsuboi, K K</creatorcontrib><creatorcontrib>Edmunds, N H</creatorcontrib><creatorcontrib>Kwong, L K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tsuboi, K K</au><au>Edmunds, N H</au><au>Kwong, L K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective inhibition of pyrimidine biosynthesis and effect on proliferative growth of colonic cancer cells</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1977-09</date><risdate>1977</risdate><volume>37</volume><issue>9</issue><spage>3080</spage><epage>3087</epage><pages>3080-3087</pages><issn>0008-5472</issn><abstract>A highly selective inhibition of de novo pyrimidine synthesis in the intact cell has been demonstrated by the action of N-(phosphonacetyl)-L-aspartate (PALA), a transition-state analog inhibitor of the reaction catalyzed by asparate transcarbamylase. The effect of pyrimidine deprivation induced by this agent on the viability and survival of human normal (WI-38) and colonic cancer cells (HT-29) was examined. The PALA-treated, pyrimidine-deprived cells failed to grow but demonstrated a normal rate of glucose utilization with impaired glycogen synthesis. Pyrimidine deprivation and lack of cell growth were maintained long after PALA removal. Growth inhibition of HT-29 cells by PALA was found to reflect an apparent steady state between newly formed and dying cells induced by limited pyrimidine availability. The highly selective nature of PALA action was confirmed by the ability of an exogenous source of pyrimidine to restore the normal growth pattern of the cell. Significant antitumor activity of PALA was found against a transplantable colonic tumor (line 26) carried in mice.</abstract><cop>United States</cop><pmid>884665</pmid><tpages>8</tpages></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 1977-09, Vol.37 (9), p.3080-3087 |
| issn | 0008-5472 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Aspartic Acid - administration & dosage Aspartic Acid - analogs & derivatives Aspartic Acid - pharmacology Cell Division - drug effects Cells, Cultured Colonic Neoplasms - drug therapy Colonic Neoplasms - metabolism Colonic Neoplasms - pathology DNA, Neoplasm - biosynthesis Humans Kinetics Mice Mice, Inbred BALB C Neoplasm Transplantation Neoplasms, Experimental - drug therapy Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Organophosphorus Compounds - administration & dosage Organophosphorus Compounds - pharmacology Pyrimidines - biosynthesis Pyrimidines - pharmacology Transplantation, Isogeneic Uridine - pharmacology |
| title | Selective inhibition of pyrimidine biosynthesis and effect on proliferative growth of colonic cancer cells |
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