Therapeutic effects of a 186Re-complex-conjugated bisphosphonate for the palliation of metastatic bone pain in an animal model.
Previously, based on the concept of bifunctional radiopharmaceuticals, we developed a highly stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re-MAG3-HBP), for the treatment of painful bone metastases. This agent showed a superior biodistribution as a bone-seeking agent in normal mice when compared with (186)Re-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP). In this study, we evaluated the therapeutic effects of (186)Re-MAG3-HBP using an animal model of bone metastasis.


METHODS
The model was prepared by injecting syngeneic MRMT-1 mammary tumor cells into the left tibia of female Sprague-Dawley rats. (186)Re-MAG3-HBP (55.5, 111, or 222 MBq/kg) or (186)Re-HEDP (55.5 MBq/kg) was then administered intravenously 21 d later. To evaluate the therapeutic effects and side effects, tumor size and peripheral blood cell counts were determined. Palliation of bone pain was evaluated by a von Frey filament test.


RESULTS
In the rats treated with (186)Re-HEDP, tumor growth was comparable with that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Allodynia induced by bone metastasis was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective.


CONCLUSIONS
These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent for the palliation of metastatic bone pain.
Ogawa
Kazuma
K
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Mukai
Takahiro
T
Asano
Daigo
D
Kawashima
Hidekazu
H
Kinuya
Seigo
S
Shiba
Kazuhiro
K
Hashimoto
Kazuyuki
K
Mori
Hirofumi
H
Saji
Hideo
H
D000818:Animals; D001859:Bone Neoplasms / Q000532:radiotherapy*; D001842:Bone and Bones / Q000528:radiation effects*; D004164:Diphosphonates / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000532:radiotherapy; D051379:Mice; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000737:chemistry* / Q000627:therapeutic use*; D010146:Pain; D011868:Radioisotopes / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012211:Rhenium / Q000627:therapeutic use*; D013997:Time Factors
C517422:(((((4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl)carbamoylmethyl)carbamoylmethyl)carbamoylmethanethiolate)oxorhenium(V); D004164:Diphosphonates; D009942:Organometallic Compounds; D011868:Radioisotopes; D012211:Rhenium