title: A conjugate of gemcitabine with bisphosphonate (Gem/BP) shows potential as a targeted bone-specific therapeutic agent in an animal model of human breast cancer bone metastases.
abstract: Bone metastases in advanced breast cancer patients remains a significant treatment challenge. Bisphosphonates are now a routine first line treatment for prevention and treatment of skeletal damage caused by malignancies and, moreover, have shown an ability to transport therapeutic drugs to the bone. Here, we describe the effect of a conjugate between the potent anticancer drug gemcitabine and a bisphosphonate molecule (Gem/BP) in an animal model of breast cancer metastases. We have previously demonstrated the targeting of this compound to bone in normal mice using an analog labeled with the radionuclide 99mTc. Using a bone metastasis model in nude mice produced by intracardiac injection of the human breast cancer cell line MDA-MB-231BO, we examined the effect of Gem/BP and gemcitabine in reducing the frequency and severity of osteolytic bone lesions. High-resolution radiographs and microPET images showed that Gem/ BP reduced the number and size of bone metastases relative to the gemcitabine-treated and the untreated control groups. Histological examination of the humeri and femurs of the control and gemcitabine groups revealed large metastatic cancer lesions in the outer and inner cortices and the medullary cavities. In contrast, Gem/BP-treated mice showed occasional small wedge-shaped metastases under the periosteum of the outer cortex and very occasionally in the medulla. These findings suggest that Gem/BP should be further evaluated for use in the treatment of bone metastases in breast cancer.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: A A
authors.initials: AA
authors.lastname: El-Mabhouh
authors.forename: P N
authors.initials: PN
authors.lastname: Nation
authors.forename: J T
authors.initials: JT
authors.lastname: Abele
authors.forename: T
authors.initials: T
authors.lastname: Riauka
authors.forename: E
authors.initials: E
authors.lastname: Postema
authors.forename: A J B
authors.initials: AJ
authors.lastname: McEwan
authors.forename: J R
authors.initials: JR
authors.lastname: Mercer
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000556:secondary; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D002118:Calcium / Q000097:blood; D003404:Creatinine / Q000097:blood; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004164:Diphosphonates / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D013667:Technetium; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004164:Diphosphonates; D003841:Deoxycytidine; D013667:Technetium; D003404:Creatinine; D002118:Calcium; D000093542:Gemcitabine