Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity
DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance...
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| Veröffentlicht in: | British journal of cancer 2002-09, Vol.87 (6), p.665-672 |
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| creator | van Hattum, A H Hoogsteen, I J Schlüper, H M M Maliepaard, M Scheffer, G L Scheper, R J Kohlhagen, G Pommier, Y Pinedo, H M Boven, E |
| description | DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor=9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor =34), SN-38 (resistance factor =47), mitoxantrone (resistance factor =59) and doxorubicin (resistance factor =2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRP1, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells.
In vivo
experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38. |
| doi_str_mv | 10.1038/sj.bjc.6600508 |
| format | Article |
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In vivo
experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/sj.bjc.6600508</identifier><identifier>PMID: 12237778</identifier><identifier>CODEN: BJCAAI</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Acridines - pharmacology ; Animals ; Antigens, CD - metabolism ; Antineoplastic Agents, Phytogenic - administration & dosage ; Antineoplastic Agents, Phytogenic - therapeutic use ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Camptothecin - administration & dosage ; Camptothecin - analogs & derivatives ; Camptothecin - therapeutic use ; Cancer Research ; Cell Division - drug effects ; Cell Division - physiology ; DNA Topoisomerases, Type I - genetics ; DNA Topoisomerases, Type I - metabolism ; Drug Resistance ; Drug Resistance, Neoplasm ; Epidemiology ; Experimental Therapeutics ; Female ; Humans ; Immunoenzyme Techniques ; Isoquinolines - pharmacology ; Membrane Glycoproteins ; Mice ; Mice, Nude ; Molecular Medicine ; Mutation ; Neoplasm Proteins - metabolism ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - pathology ; Oncology ; Ovarian Neoplasms - drug therapy ; Tetrahydroisoquinolines ; Tetraspanin 29 ; Tetrazolium Salts ; Thiazoles ; Topoisomerase I Inhibitors ; Tumor Cells, Cultured - cytology ; Tumor Cells, Cultured - drug effects</subject><ispartof>British journal of cancer, 2002-09, Vol.87 (6), p.665-672</ispartof><rights>The Author(s) 2002</rights><rights>Copyright Nature Publishing Group Sep 9, 2002</rights><rights>Copyright © 2002 Cancer Research UK 2002 Cancer Research UK</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3698-f0230a401281df6a2cd41e2e4671305500043011e0d2ae54743cd88a64f2f4fd3</citedby><cites>FETCH-LOGICAL-c3698-f0230a401281df6a2cd41e2e4671305500043011e0d2ae54743cd88a64f2f4fd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364245/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364245/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12237778$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van Hattum, A H</creatorcontrib><creatorcontrib>Hoogsteen, I J</creatorcontrib><creatorcontrib>Schlüper, H M M</creatorcontrib><creatorcontrib>Maliepaard, M</creatorcontrib><creatorcontrib>Scheffer, G L</creatorcontrib><creatorcontrib>Scheper, R J</creatorcontrib><creatorcontrib>Kohlhagen, G</creatorcontrib><creatorcontrib>Pommier, Y</creatorcontrib><creatorcontrib>Pinedo, H M</creatorcontrib><creatorcontrib>Boven, E</creatorcontrib><title>Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor=9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor =34), SN-38 (resistance factor =47), mitoxantrone (resistance factor =59) and doxorubicin (resistance factor =2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRP1, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells.
In vivo
experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.</description><subject>Acridines - pharmacology</subject><subject>Animals</subject><subject>Antigens, CD - metabolism</subject><subject>Antineoplastic Agents, Phytogenic - administration & dosage</subject><subject>Antineoplastic Agents, Phytogenic - therapeutic use</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</subject><subject>ATP Binding Cassette Transporter, Subfamily G, Member 2</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Camptothecin - administration & dosage</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - therapeutic use</subject><subject>Cancer Research</subject><subject>Cell Division - drug effects</subject><subject>Cell Division - physiology</subject><subject>DNA Topoisomerases, Type I - genetics</subject><subject>DNA Topoisomerases, Type I - metabolism</subject><subject>Drug Resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Epidemiology</subject><subject>Experimental Therapeutics</subject><subject>Female</subject><subject>Humans</subject><subject>Immunoenzyme Techniques</subject><subject>Isoquinolines - pharmacology</subject><subject>Membrane Glycoproteins</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular Medicine</subject><subject>Mutation</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Oncology</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Tetrahydroisoquinolines</subject><subject>Tetraspanin 29</subject><subject>Tetrazolium Salts</subject><subject>Thiazoles</subject><subject>Topoisomerase I Inhibitors</subject><subject>Tumor Cells, Cultured - 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pharmacology</topic><topic>Membrane Glycoproteins</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Molecular Medicine</topic><topic>Mutation</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Oncology</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Tetrahydroisoquinolines</topic><topic>Tetraspanin 29</topic><topic>Tetrazolium Salts</topic><topic>Thiazoles</topic><topic>Topoisomerase I Inhibitors</topic><topic>Tumor Cells, Cultured - cytology</topic><topic>Tumor Cells, Cultured - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van Hattum, A H</creatorcontrib><creatorcontrib>Hoogsteen, I J</creatorcontrib><creatorcontrib>Schlüper, H M M</creatorcontrib><creatorcontrib>Maliepaard, M</creatorcontrib><creatorcontrib>Scheffer, G L</creatorcontrib><creatorcontrib>Scheper, R J</creatorcontrib><creatorcontrib>Kohlhagen, G</creatorcontrib><creatorcontrib>Pommier, Y</creatorcontrib><creatorcontrib>Pinedo, H M</creatorcontrib><creatorcontrib>Boven, E</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van Hattum, A H</au><au>Hoogsteen, I J</au><au>Schlüper, H M M</au><au>Maliepaard, M</au><au>Scheffer, G L</au><au>Scheper, R J</au><au>Kohlhagen, G</au><au>Pommier, Y</au><au>Pinedo, H M</au><au>Boven, E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2002-09-09</date><risdate>2002</risdate><volume>87</volume><issue>6</issue><spage>665</spage><epage>672</epage><pages>665-672</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><coden>BJCAAI</coden><abstract>DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor=9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor =34), SN-38 (resistance factor =47), mitoxantrone (resistance factor =59) and doxorubicin (resistance factor =2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRP1, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells.
In vivo
experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>12237778</pmid><doi>10.1038/sj.bjc.6600508</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acridines - pharmacology Animals Antigens, CD - metabolism Antineoplastic Agents, Phytogenic - administration & dosage Antineoplastic Agents, Phytogenic - therapeutic use ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-Binding Cassette Transporters - metabolism Biomedical and Life Sciences Biomedicine Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Camptothecin - administration & dosage Camptothecin - analogs & derivatives Camptothecin - therapeutic use Cancer Research Cell Division - drug effects Cell Division - physiology DNA Topoisomerases, Type I - genetics DNA Topoisomerases, Type I - metabolism Drug Resistance Drug Resistance, Neoplasm Epidemiology Experimental Therapeutics Female Humans Immunoenzyme Techniques Isoquinolines - pharmacology Membrane Glycoproteins Mice Mice, Nude Molecular Medicine Mutation Neoplasm Proteins - metabolism Neoplasms, Experimental - drug therapy Neoplasms, Experimental - pathology Oncology Ovarian Neoplasms - drug therapy Tetrahydroisoquinolines Tetraspanin 29 Tetrazolium Salts Thiazoles Topoisomerase I Inhibitors Tumor Cells, Cultured - cytology Tumor Cells, Cultured - drug effects |
| title | Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity |
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