In vitro and in vivo toxicity of 5-FdU-alendronate

• Verfasst von: Schott, Sarah [VerfasserIn]
• Verfasst von: Vallet, Sonia [VerfasserIn]
• Titel: In vitro and in vivo toxicity of 5-FdU-alendronate
• Titelzusatz: a novel cytotoxic bone-seeking duplex drug against bone metastasis
• Verf.angabe: Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch
• Umfang: 11 S.
• Fussnoten: Gesehen am 22.02.2017
• Titel Quelle: Enthalten in: Investigational new drugs
• Jahr Quelle: 2015
• Band/Heft Quelle: 33(2015), 4, S. 816-826
• ISSN Quelle: 1573-0646
• DOI: doi:10.1007/s10637-015-0253-3
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 155369550X

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 ametastatic 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.