Abstract
Patients with cancer-induced bone disease, including primary bone cancers such as osteosarcoma (OS) and metastases from other tissues of origin, present a high unmet medical need. We present a potential therapeutic approach built upon a proven bone-targeting bisphosphonate conjugate platform with the known synergies of gemcitabine (GEM) and docetaxel (DTX). The synthesis of rationally designed GEM-IB, the conjugate of GEM-5'-phosphate with ibandronate (IB), is presented. GEM-IB as a single agent or in combination with DTX demonstrated reduced tumor burden, preservation of the bone architecture, and improved the survival in a murine model of OS. This is the first demonstration of a bone-targeting conjugate in combination with a second drug to create effective drug ratios in the bone compartment.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Bone Neoplasms* / drug therapy
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Bone Neoplasms* / pathology
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Cell Line, Tumor
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Deoxycytidine* / administration & dosage
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Deoxycytidine* / analogs & derivatives
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Deoxycytidine* / chemistry
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Deoxycytidine* / pharmacology
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Deoxycytidine* / therapeutic use
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Diphosphonates* / chemistry
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Diphosphonates* / pharmacology
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Diphosphonates* / therapeutic use
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Docetaxel* / chemistry
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Docetaxel* / pharmacology
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Docetaxel* / therapeutic use
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Female
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Gemcitabine*
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Humans
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Ibandronic Acid* / pharmacology
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Ibandronic Acid* / therapeutic use
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Mice
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Osteosarcoma / drug therapy
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Osteosarcoma / pathology
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Taxoids* / administration & dosage
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Taxoids* / chemistry
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Taxoids* / pharmacology
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Taxoids* / therapeutic use
Substances
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Gemcitabine
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Deoxycytidine
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Docetaxel
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Taxoids
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Ibandronic Acid
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Diphosphonates