Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases
| Autor: | Sabine Fuchs, Anna Trauzold, Philipp Kneissl, Christian Schem, Robert J. Tower, Christine Desel, Anna-Christina Rambow, Claus C. Glüer, Sanjay Tiwari, Sarah Schott, Thorsten Heilmann, Maaz Zuhayra, Timo Damm, Graeme M. Campbell |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
biology medicine.drug_class business.industry Endocrinology Diabetes and Metabolism medicine.medical_treatment Bisphosphonate Pharmacology medicine.disease Antimetabolite Bone resorption 03 medical and health sciences 030104 developmental biology Breast cancer In vivo medicine Adjuvant therapy Osteocalcin biology.protein Protein prenylation Orthopedics and Sports Medicine business |
| Zdroj: | Journal of Bone and Mineral Research. 32:536-548 |
| ISSN: | 0884-0431 |
| Popis: | Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p |
| Databáze: | OpenAIRE |
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