Selective tumor apoptosis by MF13, L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester, a new sarcolysin containing tripeptide
ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activi...
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Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1997-11, Vol.57 (21), p.4795-4802 |
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description | ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2-5 times higher than that of sarcolysin [(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine] against all leukemias and lymphomas, ID50 0.5-0.9 microM, and against human solid tumors, ID50 0.4-2.1 microM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID50 0.5 microM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180-200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID50, 13.3 microM without and 11 microM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent. |
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F ; BEKESI, J. G</creator><creatorcontrib>ROBOZ, J ; JIANG, J ; HOLLAND, J. F ; BEKESI, J. G</creatorcontrib><description>ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2-5 times higher than that of sarcolysin [(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine] against all leukemias and lymphomas, ID50 0.5-0.9 microM, and against human solid tumors, ID50 0.4-2.1 microM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID50 0.5 microM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180-200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID50, 13.3 microM without and 11 microM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 9354441</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents, Alkylating - therapeutic use ; Apoptosis - drug effects ; Apoptosis - genetics ; Biological and medical sciences ; Cell Survival ; Chemotherapy ; DNA Fragmentation ; DNA, Neoplasm - drug effects ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Flow Cytometry ; Humans ; Lethal Dose 50 ; Leukemia - drug therapy ; Leukemia - pathology ; Leukemia L1210 - drug therapy ; Leukemia L1210 - pathology ; Lymphoma - drug therapy ; Lymphoma - pathology ; Medical sciences ; Melphalan - pharmacology ; Methotrexate - pharmacology ; Mice ; Neoplasms - drug therapy ; Neoplasms - pathology ; Oligopeptides - therapeutic use ; Pharmacology. Drug treatments ; Tumor Cells, Cultured - drug effects ; Tumor Cells, Cultured - pathology</subject><ispartof>Cancer research (Chicago, Ill.), 1997-11, Vol.57 (21), p.4795-4802</ispartof><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2067808$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9354441$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ROBOZ, J</creatorcontrib><creatorcontrib>JIANG, J</creatorcontrib><creatorcontrib>HOLLAND, J. F</creatorcontrib><creatorcontrib>BEKESI, J. G</creatorcontrib><title>Selective tumor apoptosis by MF13, L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester, a new sarcolysin containing tripeptide</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2-5 times higher than that of sarcolysin [(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine] against all leukemias and lymphomas, ID50 0.5-0.9 microM, and against human solid tumors, ID50 0.4-2.1 microM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID50 0.5 microM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180-200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID50, 13.3 microM without and 11 microM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Alkylating - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Biological and medical sciences</subject><subject>Cell Survival</subject><subject>Chemotherapy</subject><subject>DNA Fragmentation</subject><subject>DNA, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Lethal Dose 50</subject><subject>Leukemia - drug therapy</subject><subject>Leukemia - pathology</subject><subject>Leukemia L1210 - drug therapy</subject><subject>Leukemia L1210 - pathology</subject><subject>Lymphoma - drug therapy</subject><subject>Lymphoma - pathology</subject><subject>Medical sciences</subject><subject>Melphalan - pharmacology</subject><subject>Methotrexate - pharmacology</subject><subject>Mice</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Oligopeptides - therapeutic use</subject><subject>Pharmacology. Drug treatments</subject><subject>Tumor Cells, Cultured - drug effects</subject><subject>Tumor Cells, Cultured - pathology</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kNFKwzAUhoMoc04fQciFFwoLNG2SdpcynAoTL9QrkXGaJjaSJiXJJn0PH9gyh1eHn__jh-8coSnlRUVKxvgxmmZZVhHOyvwUncX4NUZOMz5Bk0XBGWN0in5elFUymZ3Cadv5gKH3ffLRRFwP-GlFizlekz54O1iyJh15r028lq31wavUDvYGOuP8B-lb5QYLFtwedD7swBqn8J7CKiYV5hiwU984QpDjYDQOS-8SGGfcJ07B9KpPplHn6ESDjericGfobXX3unwg6-f7x-XtmrS5WKRRTBZUwejBmjynteRNLrQWQmqQjag0y6godKNpWXMKRbPIalC54gL0aF8WM3T5t9tv6041mz6YDsKwOXxn7K8OPUQJVgdw0sR_LM9EWWVV8QuCE3H9</recordid><startdate>19971101</startdate><enddate>19971101</enddate><creator>ROBOZ, J</creator><creator>JIANG, J</creator><creator>HOLLAND, J. F</creator><creator>BEKESI, J. G</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>19971101</creationdate><title>Selective tumor apoptosis by MF13, L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester, a new sarcolysin containing tripeptide</title><author>ROBOZ, J ; JIANG, J ; HOLLAND, J. F ; BEKESI, J. G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-54c31ea4414d221bc5d26ff66cfacd68f40163fdf17b51a3d90bae2e56af44473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Alkylating - therapeutic use</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Biological and medical sciences</topic><topic>Cell Survival</topic><topic>Chemotherapy</topic><topic>DNA Fragmentation</topic><topic>DNA, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Flow Cytometry</topic><topic>Humans</topic><topic>Lethal Dose 50</topic><topic>Leukemia - drug therapy</topic><topic>Leukemia - pathology</topic><topic>Leukemia L1210 - drug therapy</topic><topic>Leukemia L1210 - pathology</topic><topic>Lymphoma - drug therapy</topic><topic>Lymphoma - pathology</topic><topic>Medical sciences</topic><topic>Melphalan - pharmacology</topic><topic>Methotrexate - pharmacology</topic><topic>Mice</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>Oligopeptides - therapeutic use</topic><topic>Pharmacology. Drug treatments</topic><topic>Tumor Cells, Cultured - drug effects</topic><topic>Tumor Cells, Cultured - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ROBOZ, J</creatorcontrib><creatorcontrib>JIANG, J</creatorcontrib><creatorcontrib>HOLLAND, J. F</creatorcontrib><creatorcontrib>BEKESI, J. G</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ROBOZ, J</au><au>JIANG, J</au><au>HOLLAND, J. F</au><au>BEKESI, J. G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective tumor apoptosis by MF13, L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester, a new sarcolysin containing tripeptide</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1997-11-01</date><risdate>1997</risdate><volume>57</volume><issue>21</issue><spage>4795</spage><epage>4802</epage><pages>4795-4802</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2-5 times higher than that of sarcolysin [(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine] against all leukemias and lymphomas, ID50 0.5-0.9 microM, and against human solid tumors, ID50 0.4-2.1 microM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID50 0.5 microM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180-200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID50, 13.3 microM without and 11 microM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>9354441</pmid><tpages>8</tpages></addata></record> |
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subjects | Animals Antineoplastic agents Antineoplastic Agents, Alkylating - therapeutic use Apoptosis - drug effects Apoptosis - genetics Biological and medical sciences Cell Survival Chemotherapy DNA Fragmentation DNA, Neoplasm - drug effects Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Flow Cytometry Humans Lethal Dose 50 Leukemia - drug therapy Leukemia - pathology Leukemia L1210 - drug therapy Leukemia L1210 - pathology Lymphoma - drug therapy Lymphoma - pathology Medical sciences Melphalan - pharmacology Methotrexate - pharmacology Mice Neoplasms - drug therapy Neoplasms - pathology Oligopeptides - therapeutic use Pharmacology. Drug treatments Tumor Cells, Cultured - drug effects Tumor Cells, Cultured - pathology |
title | Selective tumor apoptosis by MF13, L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester, a new sarcolysin containing tripeptide |
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