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.
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Authors | Amal El-Mabhouh, Christo Angelov, Alexander McEwan, Guofeng Jia, John Mercer |
Journal | Cancer biotherapy & radiopharmaceuticals
(Cancer Biother Radiopharm)
Vol. 19
Issue 5
Pg. 627-40
(Oct 2004)
ISSN: 1084-9785 [Print] United States |
PMID | 15650456
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites, Antineoplastic
- Diphosphonates
- Pentetic Acid
- Fluorouracil
- Technetium Tc 99m Pentetate
- Technetium Tc 99m Medronate
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Topics |
- Animals
- Antimetabolites, Antineoplastic
(pharmacology)
- Bone Neoplasms
(drug therapy)
- Diphosphonates
(chemistry, therapeutic use)
- Female
- Fluorouracil
(pharmacology)
- Humans
- Mice
- Mice, Inbred BALB C
- Models, Chemical
- Neoplasm Metastasis
- Neoplasm Transplantation
- Neoplasms, Experimental
- Pentetic Acid
(pharmacology)
- Technetium Tc 99m Medronate
(pharmacology)
- Technetium Tc 99m Pentetate
(pharmacology)
- Time Factors
- Tissue Distribution
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