A promising approach for treatment of tumor-induced bone diseases: Utilizing bisphosphonate derivatives of nucleoside antimetabolites
| Autor: | Harri Lönnberg, Luis Sanchez-Perez, Vivian Negron, David P Sebesta, Shawn Zinnen, Monica M. Reinholz, Diane F. Jelinek, Anthony J. Croatt, Amylou C. Dueck, Leslie M. Jonart, Henry B F Hal Dixon, James N. Ingle, Wilma L. Lingle, Thomas C. Spelsberg, Toshiyuki Yoneda, Gregory G. Reinholz, David Dingli, Kathleen A Kitzmann, Karl A. Nath, Abdalla K Abdalla, Bonnie K. Arendt, Stephen J. Russell, Alexander Karpeisky, Amy K Bruzek |
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| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Pathology Histology Bone density Bone disease Antimetabolites Physiology medicine.drug_class Endocrinology Diabetes and Metabolism medicine.medical_treatment Kaplan-Meier Estimate Mice SCID Antimetabolite Bone and Bones Article Mice Bone Density Cell Line Tumor Neoplasms Internal medicine Animals Humans Medicine Femur Multiple myeloma Cell Proliferation Mice Inbred BALB C Chemotherapy Diphosphonates business.industry Bone cancer Nucleosides Organ Size Bisphosphonate medicine.disease Xenograft Model Antitumor Assays Tumor Burden Endocrinology Bone Diseases Multiple Myeloma business Neoplasm Transplantation |
| Zdroj: | Bone. 47:12-22 |
| ISSN: | 8756-3282 |
| Popis: | Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced anti-resorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5'-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1alpha multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 microg/day; s.c.) reduced the incidence of bone metastases to 40% (4/10), compared to 90% (9/10; p=0.057) and 100% (5/5; p=0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice (p=0.021, p=0.017, respectively). MBC-11 and zoledronate (0.04 microg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice (p=0.005, p |
| Databáze: | OpenAIRE |
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