In vitro and in vivo toxicity of 5-FdU-alendronate : a novel cytotoxic bone-seeking duplex drug against bone metastasis

SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-...
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Autor*in:	Schott, Sarah - 1981- [verfasserIn] Vallet, Sonia - 1976- [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	August 2015

Anmerkung:	Gesehen am 22.02.2017
Umfang:	11

Übergeordnetes Werk:	Enthalten in: Investigational new drugs - Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983, 33(2015), 4, Seite 816-826
Übergeordnetes Werk:	volume:33 ; year:2015 ; number:4 ; pages:816-826 ; extent:11

Links:	Volltext Volltext

DOI / URN:	10.1007/s10637-015-0253-3

Katalog-ID:	155369550X

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245	1	0	\|a In vitro and in vivo toxicity of 5-FdU-alendronate \|b a novel cytotoxic bone-seeking duplex drug against bone metastasis \|c Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch
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520			\|a SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation.
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912			\|a GBV_ILN_2070
912			\|a GBV_ILN_2086
912			\|a GBV_ILN_2088
912			\|a GBV_ILN_2093
912			\|a GBV_ILN_2106
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Indexfelder

author_variant	s s ss s v sv
matchkey_str	article:15730646:2015----::niradniooiiyffu
oclc_num	1340960493
hierarchy_sort_str	August 2015
publishDate	2015
allfields	10.1007/s10637-015-0253-3 doi (DE-627)155369550X (DE-576)483695505 (DE-599)BSZ483695505 (OCoLC)1340960493 DE-627 ger DE-627 rda eng Schott, Sarah 1981- verfasserin (DE-588)133730816 (DE-627)552697281 (DE-576)27460678X aut In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch August 2015 11 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 22.02.2017 SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Vallet, Sonia 1976- verfasserin (DE-588)105867207X (DE-627)797396403 (DE-576)414826493 aut Enthalten in Investigational new drugs Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983 33(2015), 4, Seite 816-826 Online-Ressource (DE-627)320481492 (DE-600)2009846-7 (DE-576)121191028 1573-0646 nnns volume:33 year:2015 number:4 pages:816-826 extent:11 http://dx.doi.org/10.1007/s10637-015-0253-3 Verlag Resolving-System Volltext https://link.springer.com/article/10.1007/s10637-015-0253-3 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 33 2015 4 816-826 11 2013 01 DE-16-250 2954538864 00 --%%-- --%%-- --%%-- --%%-- l01 22-02-17 2013 01 DE-16-250 00 s hd2015 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_7 2013 01 DE-16-250 03 s s_11 2013 01 DE-16-250 04 p (DE-627)1448427479 Schott, Sarah 2013 01 DE-16-250 04 k (DE-627)1416740961 Universitäts-Frauenklinik 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1484826825 Vallet, Sonia 2013 01 DE-16-250 05 k (DE-627)1416740783 Medizinische Universitätsklinik und Poliklinik 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2
spelling	10.1007/s10637-015-0253-3 doi (DE-627)155369550X (DE-576)483695505 (DE-599)BSZ483695505 (OCoLC)1340960493 DE-627 ger DE-627 rda eng Schott, Sarah 1981- verfasserin (DE-588)133730816 (DE-627)552697281 (DE-576)27460678X aut In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch August 2015 11 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 22.02.2017 SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Vallet, Sonia 1976- verfasserin (DE-588)105867207X (DE-627)797396403 (DE-576)414826493 aut Enthalten in Investigational new drugs Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983 33(2015), 4, Seite 816-826 Online-Ressource (DE-627)320481492 (DE-600)2009846-7 (DE-576)121191028 1573-0646 nnns volume:33 year:2015 number:4 pages:816-826 extent:11 http://dx.doi.org/10.1007/s10637-015-0253-3 Verlag Resolving-System Volltext https://link.springer.com/article/10.1007/s10637-015-0253-3 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 33 2015 4 816-826 11 2013 01 DE-16-250 2954538864 00 --%%-- --%%-- --%%-- --%%-- l01 22-02-17 2013 01 DE-16-250 00 s hd2015 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_7 2013 01 DE-16-250 03 s s_11 2013 01 DE-16-250 04 p (DE-627)1448427479 Schott, Sarah 2013 01 DE-16-250 04 k (DE-627)1416740961 Universitäts-Frauenklinik 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1484826825 Vallet, Sonia 2013 01 DE-16-250 05 k (DE-627)1416740783 Medizinische Universitätsklinik und Poliklinik 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2
allfields_unstemmed	10.1007/s10637-015-0253-3 doi (DE-627)155369550X (DE-576)483695505 (DE-599)BSZ483695505 (OCoLC)1340960493 DE-627 ger DE-627 rda eng Schott, Sarah 1981- verfasserin (DE-588)133730816 (DE-627)552697281 (DE-576)27460678X aut In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch August 2015 11 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 22.02.2017 SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Vallet, Sonia 1976- verfasserin (DE-588)105867207X (DE-627)797396403 (DE-576)414826493 aut Enthalten in Investigational new drugs Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983 33(2015), 4, Seite 816-826 Online-Ressource (DE-627)320481492 (DE-600)2009846-7 (DE-576)121191028 1573-0646 nnns volume:33 year:2015 number:4 pages:816-826 extent:11 http://dx.doi.org/10.1007/s10637-015-0253-3 Verlag Resolving-System Volltext https://link.springer.com/article/10.1007/s10637-015-0253-3 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 33 2015 4 816-826 11 2013 01 DE-16-250 2954538864 00 --%%-- --%%-- --%%-- --%%-- l01 22-02-17 2013 01 DE-16-250 00 s hd2015 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_7 2013 01 DE-16-250 03 s s_11 2013 01 DE-16-250 04 p (DE-627)1448427479 Schott, Sarah 2013 01 DE-16-250 04 k (DE-627)1416740961 Universitäts-Frauenklinik 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1484826825 Vallet, Sonia 2013 01 DE-16-250 05 k (DE-627)1416740783 Medizinische Universitätsklinik und Poliklinik 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2
allfieldsGer	10.1007/s10637-015-0253-3 doi (DE-627)155369550X (DE-576)483695505 (DE-599)BSZ483695505 (OCoLC)1340960493 DE-627 ger DE-627 rda eng Schott, Sarah 1981- verfasserin (DE-588)133730816 (DE-627)552697281 (DE-576)27460678X aut In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch August 2015 11 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 22.02.2017 SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Vallet, Sonia 1976- verfasserin (DE-588)105867207X (DE-627)797396403 (DE-576)414826493 aut Enthalten in Investigational new drugs Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983 33(2015), 4, Seite 816-826 Online-Ressource (DE-627)320481492 (DE-600)2009846-7 (DE-576)121191028 1573-0646 nnns volume:33 year:2015 number:4 pages:816-826 extent:11 http://dx.doi.org/10.1007/s10637-015-0253-3 Verlag Resolving-System Volltext https://link.springer.com/article/10.1007/s10637-015-0253-3 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 33 2015 4 816-826 11 2013 01 DE-16-250 2954538864 00 --%%-- --%%-- --%%-- --%%-- l01 22-02-17 2013 01 DE-16-250 00 s hd2015 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_7 2013 01 DE-16-250 03 s s_11 2013 01 DE-16-250 04 p (DE-627)1448427479 Schott, Sarah 2013 01 DE-16-250 04 k (DE-627)1416740961 Universitäts-Frauenklinik 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1484826825 Vallet, Sonia 2013 01 DE-16-250 05 k (DE-627)1416740783 Medizinische Universitätsklinik und Poliklinik 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2
allfieldsSound	10.1007/s10637-015-0253-3 doi (DE-627)155369550X (DE-576)483695505 (DE-599)BSZ483695505 (OCoLC)1340960493 DE-627 ger DE-627 rda eng Schott, Sarah 1981- verfasserin (DE-588)133730816 (DE-627)552697281 (DE-576)27460678X aut In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch August 2015 11 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 22.02.2017 SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Vallet, Sonia 1976- verfasserin (DE-588)105867207X (DE-627)797396403 (DE-576)414826493 aut Enthalten in Investigational new drugs Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983 33(2015), 4, Seite 816-826 Online-Ressource (DE-627)320481492 (DE-600)2009846-7 (DE-576)121191028 1573-0646 nnns volume:33 year:2015 number:4 pages:816-826 extent:11 http://dx.doi.org/10.1007/s10637-015-0253-3 Verlag Resolving-System Volltext https://link.springer.com/article/10.1007/s10637-015-0253-3 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 33 2015 4 816-826 11 2013 01 DE-16-250 2954538864 00 --%%-- --%%-- --%%-- --%%-- l01 22-02-17 2013 01 DE-16-250 00 s hd2015 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_7 2013 01 DE-16-250 03 s s_11 2013 01 DE-16-250 04 p (DE-627)1448427479 Schott, Sarah 2013 01 DE-16-250 04 k (DE-627)1416740961 Universitäts-Frauenklinik 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1484826825 Vallet, Sonia 2013 01 DE-16-250 05 k (DE-627)1416740783 Medizinische Universitätsklinik und Poliklinik 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2
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source	Enthalten in Investigational new drugs 33(2015), 4, Seite 816-826 volume:33 year:2015 number:4 pages:816-826 extent:11
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fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">155369550X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230428174647.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">170222s2015 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s10637-015-0253-3</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)155369550X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-576)483695505</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)BSZ483695505</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(OCoLC)1340960493</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rda</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Schott, Sarah</subfield><subfield code="d">1981-</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(DE-588)133730816</subfield><subfield code="0">(DE-627)552697281</subfield><subfield code="0">(DE-576)27460678X</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">In vitro and in vivo toxicity of 5-FdU-alendronate</subfield><subfield code="b">a novel cytotoxic bone-seeking duplex drug against bone metastasis</subfield><subfield code="c">Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">August 2015</subfield></datafield><datafield tag="300" ind1=" " ind2=" "><subfield code="a">11</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">Gesehen am 22.02.2017</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation.</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Vallet, Sonia</subfield><subfield code="d">1976-</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(DE-588)105867207X</subfield><subfield code="0">(DE-627)797396403</subfield><subfield code="0">(DE-576)414826493</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Investigational new drugs</subfield><subfield code="d">Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983</subfield><subfield code="g">33(2015), 4, Seite 816-826</subfield><subfield code="h">Online-Ressource</subfield><subfield code="w">(DE-627)320481492</subfield><subfield code="w">(DE-600)2009846-7</subfield><subfield code="w">(DE-576)121191028</subfield><subfield code="x">1573-0646</subfield><subfield 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title	In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis
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title_full	In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch
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title_sub	a novel cytotoxic bone-seeking duplex drug against bone metastasis
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title_sort	in vitro and in vivo toxicity of 5-fdu-alendronatea novel cytotoxic bone-seeking duplex drug against bone metastasis
title_auth	In vitro and in vivo toxicity of 5-FdU-alendronate a novel cytotoxic bone-seeking duplex drug against bone metastasis
abstract	SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Gesehen am 22.02.2017
abstractGer	SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Gesehen am 22.02.2017
abstract_unstemmed	SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. Gesehen am 22.02.2017
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title_short	In vitro and in vivo toxicity of 5-FdU-alendronate
url	http://dx.doi.org/10.1007/s10637-015-0253-3 https://link.springer.com/article/10.1007/s10637-015-0253-3
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author2	Vallet, Sonia 1976-
author2Str	Vallet, Sonia 1976-
ppnlink	320481492
GND_str_mv	Schott, Sarah Julia Schott, S. Schott, Sarah Vallet, Sonia
GND_txt_mv	Schott, Sarah Julia Schott, S. Schott, Sarah Vallet, Sonia
GND_txtF_mv	Schott, Sarah Julia Schott, S. Schott, Sarah Vallet, Sonia
mediatype_str_mv	c
isOA_txt	false
hochschulschrift_bool	false
doi_str	10.1007/s10637-015-0253-3
callnumber-a	--%%--
up_date	2024-07-04T18:24:53.183Z
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">155369550X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230428174647.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">170222s2015 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s10637-015-0253-3</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)155369550X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-576)483695505</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)BSZ483695505</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(OCoLC)1340960493</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rda</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Schott, Sarah</subfield><subfield code="d">1981-</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(DE-588)133730816</subfield><subfield code="0">(DE-627)552697281</subfield><subfield code="0">(DE-576)27460678X</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">In vitro and in vivo toxicity of 5-FdU-alendronate</subfield><subfield code="b">a novel cytotoxic bone-seeking duplex drug against bone metastasis</subfield><subfield code="c">Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">August 2015</subfield></datafield><datafield tag="300" ind1=" " ind2=" "><subfield code="a">11</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">Gesehen am 22.02.2017</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">SummaryBackground Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. 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In vitro and in vivo toxicity of 5-FdU-alendronate : a novel cytotoxic bone-seeking duplex drug against bone metastasis

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