Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats
The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly exp...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1997-10, Vol.57 (20), p.4530-4536 |
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| creator | SJÖGREN, H. O ISAKSSON, M WILLNER, D HELLSTRÖM, I HELLSTRÖM, K. E TRAIL, P. A |
| description | The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats. BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These results confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors. The findings in BN7005 further demonstrate efficacy of BR96-DOX therapy in a model in which the tumor is syngeneic and the host is immunocompetent. |
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O ; ISAKSSON, M ; WILLNER, D ; HELLSTRÖM, I ; HELLSTRÖM, K. E ; TRAIL, P. A</creator><creatorcontrib>SJÖGREN, H. O ; ISAKSSON, M ; WILLNER, D ; HELLSTRÖM, I ; HELLSTRÖM, K. E ; TRAIL, P. A</creatorcontrib><description>The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats. BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These results confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors. The findings in BN7005 further demonstrate efficacy of BR96-DOX therapy in a model in which the tumor is syngeneic and the host is immunocompetent.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 9377565</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - pathology ; Adenocarcinoma - secondary ; Animals ; Antibodies, Monoclonal - therapeutic use ; Antineoplastic agents ; Antineoplastic Agents - therapeutic use ; Biological and medical sciences ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - pathology ; Combined treatments (chemotherapy of immunotherapy associated with an other treatment) ; Doxorubicin - therapeutic use ; Female ; Humans ; Immunotoxins - therapeutic use ; Liver Neoplasms - drug therapy ; Liver Neoplasms - pathology ; Liver Neoplasms - secondary ; Medical sciences ; Mice ; Mice, Nude ; Pharmacology. Drug treatments ; Rats ; Rats, Inbred BN ; Transplantation, Heterologous ; Transplantation, Isogeneic ; Tumor Cells, Cultured</subject><ispartof>Cancer research (Chicago, Ill.), 1997-10, Vol.57 (20), p.4530-4536</ispartof><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2044924$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9377565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SJÖGREN, H. O</creatorcontrib><creatorcontrib>ISAKSSON, M</creatorcontrib><creatorcontrib>WILLNER, D</creatorcontrib><creatorcontrib>HELLSTRÖM, I</creatorcontrib><creatorcontrib>HELLSTRÖM, K. E</creatorcontrib><creatorcontrib>TRAIL, P. A</creatorcontrib><title>Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats. BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These results confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors. The findings in BN7005 further demonstrate efficacy of BR96-DOX therapy in a model in which the tumor is syngeneic and the host is immunocompetent.</description><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma - secondary</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - pathology</subject><subject>Combined treatments (chemotherapy of immunotherapy associated with an other treatment)</subject><subject>Doxorubicin - therapeutic use</subject><subject>Female</subject><subject>Humans</subject><subject>Immunotoxins - therapeutic use</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - pathology</subject><subject>Liver Neoplasms - secondary</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Inbred BN</subject><subject>Transplantation, Heterologous</subject><subject>Transplantation, Isogeneic</subject><subject>Tumor Cells, Cultured</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>eNpdkM9KAzEQxoMotVYfQcjB60KSTTbZYy3-A0EQPZfZbLZNaZKSZMW-kk9pqEXBwzAz3-_75jAnaEpFrSrJuThFU0KIqgSX7BxdpLQpq6BETNCkraUUjZiir7nPNo8uRAw62w-b9zgMWEPU1gcHVTQH3eDb17ap-vAZ4tjZArEOfjOuIBsMK7A-ZbweHfi_bMLFBXm9d1bjUsXoexwhp8OQ9n5lvCmsSP9S1rnRBx3czmTj8yF0ic4G2CZzdewz9H5_97Z4rJ5fHp4W8-dqzQjNVUO57AbWQqNZrTsgulegOsoGoNrQpm-kZIoqojjvVN-YGozUQPth0C0xop6h65-7u7Fzpl_uonUQ98vjzwq_OXJIGrZDBK9t-rUxwnnLeP0NJCt7RA</recordid><startdate>19971015</startdate><enddate>19971015</enddate><creator>SJÖGREN, H. 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A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h201t-6147bf29a6c23cba0cd8a8b12fa1ce16d67728180844b8d6e3ae7ca1dffc90e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - pathology</topic><topic>Adenocarcinoma - secondary</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - pathology</topic><topic>Combined treatments (chemotherapy of immunotherapy associated with an other treatment)</topic><topic>Doxorubicin - therapeutic use</topic><topic>Female</topic><topic>Humans</topic><topic>Immunotoxins - therapeutic use</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - pathology</topic><topic>Liver Neoplasms - secondary</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Inbred BN</topic><topic>Transplantation, Heterologous</topic><topic>Transplantation, Isogeneic</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SJÖGREN, H. O</creatorcontrib><creatorcontrib>ISAKSSON, M</creatorcontrib><creatorcontrib>WILLNER, D</creatorcontrib><creatorcontrib>HELLSTRÖM, I</creatorcontrib><creatorcontrib>HELLSTRÖM, K. E</creatorcontrib><creatorcontrib>TRAIL, P. A</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>SJÖGREN, H. O</au><au>ISAKSSON, M</au><au>WILLNER, D</au><au>HELLSTRÖM, I</au><au>HELLSTRÖM, K. E</au><au>TRAIL, P. A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1997-10-15</date><risdate>1997</risdate><volume>57</volume><issue>20</issue><spage>4530</spage><epage>4536</epage><pages>4530-4536</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats. BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These results confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors. The findings in BN7005 further demonstrate efficacy of BR96-DOX therapy in a model in which the tumor is syngeneic and the host is immunocompetent.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>9377565</pmid><tpages>7</tpages></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adenocarcinoma - drug therapy Adenocarcinoma - pathology Adenocarcinoma - secondary Animals Antibodies, Monoclonal - therapeutic use Antineoplastic agents Antineoplastic Agents - therapeutic use Biological and medical sciences Colonic Neoplasms - drug therapy Colonic Neoplasms - pathology Combined treatments (chemotherapy of immunotherapy associated with an other treatment) Doxorubicin - therapeutic use Female Humans Immunotoxins - therapeutic use Liver Neoplasms - drug therapy Liver Neoplasms - pathology Liver Neoplasms - secondary Medical sciences Mice Mice, Nude Pharmacology. Drug treatments Rats Rats, Inbred BN Transplantation, Heterologous Transplantation, Isogeneic Tumor Cells, Cultured |
| title | Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats |
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