In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis
Autor: | Seema Noor, Sanjay Tiwari, Sonia Vallet, Sarah Schott, Robert J. Tower, Christian Busch, Christian Schem |
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Rok vydání: | 2015 |
Předmět: |
Antimetabolites
Antineoplastic Pathology medicine.medical_specialty Stromal cell Cell Survival medicine.drug_class medicine.medical_treatment Mice Nude Osteoclasts Bone Neoplasms Breast Neoplasms Chick Embryo Kidney Antimetabolite Cell Line Nephrotoxicity Osteoclast Cell Line Tumor medicine Animals Humans Pharmacology (medical) Cytotoxicity Pharmacology Chemotherapy Alendronate Bone Density Conservation Agents business.industry Bone metastasis medicine.disease Metastatic breast cancer Drug Combinations medicine.anatomical_structure Oncology Cancer research Female Fluorouracil business Glomerular Filtration Rate |
Zdroj: | Investigational New Drugs. 33:816-826 |
ISSN: | 1573-0646 0167-6997 |
Popis: | Background 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. |
Databáze: | OpenAIRE |
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