title: Preclinical investigations of drug and radionuclide conjugates of bisphosphonates for the treatment of metastatic bone cancer.
abstract: The potential targeting of therapeutic bisphosphonate conjugates to bone metastatic lesions was evaluated in vivo in mice. A bisphosphonate conjugate with 5-fluorouracil was synthesized as a potential chemotherapy agent, and a bisphosphonate conjugate with diethylenetriaminepentaacetic acid (DTPA) was prepared as a potential carrier of cytotoxic radionuclides. The compounds are hypothesized to be able to deliver either high doses of radiation or a high concentration of chemotherapy agents at sites of increased osteoclastic activity in patients with bony metastases while exhibiting minimal toxicity to normal tissues. Tissue distribution studies with the 99mTc-labeled bisphosphonate conjugates with DTPA and 5-fluorouracil showed rapid blood clearance and excretion of unbound activity, clearance from most tissues, and substantial retention of the bisphosphonates in bone. For the DTPA conjugate, activity in the bone represents 13.6% of the total injected dose at 8 hours following injection, representing 54.3% of the total whole-body activity at this time period. Under the same conditions, the 5-fluorouracil conjugate showed a 17.1% bone uptake at 60.2% of the whole-body activity. This normal bone uptake predicts that high concentrations of conjugates are expected to be achieved at sites of bone metastatic disease. Chemotherapy and radiotherapy studies with these compounds in animal models of metastatic bone cancer are underway.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: El-Mabhouh
authors.forename: Christo
authors.initials: C
authors.lastname: Angelov
authors.forename: Alexander
authors.initials: A
authors.lastname: McEwan
authors.forename: Guofeng
authors.initials: G
authors.lastname: Jia
authors.forename: John
authors.initials: J
authors.lastname: Mercer
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy*; D004164:Diphosphonates / Q000737:chemistry* / Q000627:therapeutic use*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D004369:Pentetic Acid / Q000494:pharmacology; D013669:Technetium Tc 99m Medronate / Q000494:pharmacology; D016284:Technetium Tc 99m Pentetate / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D004164:Diphosphonates; D004369:Pentetic Acid; D005472:Fluorouracil; D016284:Technetium Tc 99m Pentetate; D013669:Technetium Tc 99m Medronate