Improved 223Ra Therapy with Combination Epithelial Sodium Channel Blockade
(2021) In Journal of Nuclear Medicine 62(12). p.1751-1758- Abstract
[223Ra]RaCl2 is the first approved a-particle-emitting therapy and is indicated for treatment of bonemetastatic castration-resistant prostate cancer. Approximately half the dose is absorbed into the gastrointestinal tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here,we investigated the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects. Methods: Using primary human duodenal organoids (enteroids) asin vitromodelsof the functionalgastrointestinal epithelium, we found that amiloride (epithelial sodium ion channel blocker) and NS-1619 (K+ channel activator) presented significant effects in 223Ramembranal... (More)
[223Ra]RaCl2 is the first approved a-particle-emitting therapy and is indicated for treatment of bonemetastatic castration-resistant prostate cancer. Approximately half the dose is absorbed into the gastrointestinal tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here,we investigated the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects. Methods: Using primary human duodenal organoids (enteroids) asin vitromodelsof the functionalgastrointestinal epithelium, we found that amiloride (epithelial sodium ion channel blocker) and NS-1619 (K+ channel activator) presented significant effects in 223Ramembranal transport.Radioactivedrugdistributionwas evaluated for lead combinations in vivo and in osteosarcoma and prostate cancermodels.Results:Amiloride shifted 223Ra uptake in vivo fromthe gut and nearly doubled the uptake at sites of bone remodeling. Bone tumor growth inhibition with the combination as measured by bioluminescent imaging and radiographywas significantly greater than that with single agents alone, and the combination resulted in noweight loss.Conclusion: This combination of approved agentsmay readily be implemented as a clinical approach to improve the outcomes of bonemetastatic cancer patients with the benefit of ameliorated tolerability. COPYRIGHT
(Less)
- author
- organization
- publishing date
- 2021-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Ra, amiloride, bone, gastrointestinal, ion channel
- in
- Journal of Nuclear Medicine
- volume
- 62
- issue
- 12
- pages
- 8 pages
- publisher
- Society of Nuclear Medicine
- external identifiers
-
- pmid:33837069
- scopus:85127983419
- ISSN
- 0161-5505
- DOI
- 10.2967/jnumed.121.261977
- language
- English
- LU publication?
- yes
- id
- 7052b1f3-523c-4668-8f59-c3ce8ff21e36
- date added to LUP
- 2022-06-14 14:05:57
- date last changed
- 2024-04-18 02:01:14
@article{7052b1f3-523c-4668-8f59-c3ce8ff21e36, abstract = {{<p>[223Ra]RaCl2 is the first approved a-particle-emitting therapy and is indicated for treatment of bonemetastatic castration-resistant prostate cancer. Approximately half the dose is absorbed into the gastrointestinal tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here,we investigated the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects. Methods: Using primary human duodenal organoids (enteroids) asin vitromodelsof the functionalgastrointestinal epithelium, we found that amiloride (epithelial sodium ion channel blocker) and NS-1619 (K+ channel activator) presented significant effects in 223Ramembranal transport.Radioactivedrugdistributionwas evaluated for lead combinations in vivo and in osteosarcoma and prostate cancermodels.Results:Amiloride shifted 223Ra uptake in vivo fromthe gut and nearly doubled the uptake at sites of bone remodeling. Bone tumor growth inhibition with the combination as measured by bioluminescent imaging and radiographywas significantly greater than that with single agents alone, and the combination resulted in noweight loss.Conclusion: This combination of approved agentsmay readily be implemented as a clinical approach to improve the outcomes of bonemetastatic cancer patients with the benefit of ameliorated tolerability. COPYRIGHT </p>}}, author = {{Abou, Diane S. and Fears, Amanda and Summer, Lucy and Longtine, Mark and Benabdallah, Nadia and Riddle, Ryan C. and Ulmert, David and Michalski, Jeff M. and Wahl, Richard L. and Chesner, Denise and Doucet, Michele and Zachos, Nicholas C. and Simons, Brian W. and Thorek, Daniel L.J.}}, issn = {{0161-5505}}, keywords = {{Ra; amiloride; bone; gastrointestinal; ion channel}}, language = {{eng}}, number = {{12}}, pages = {{1751--1758}}, publisher = {{Society of Nuclear Medicine}}, series = {{Journal of Nuclear Medicine}}, title = {{Improved <sup>223</sup>Ra Therapy with Combination Epithelial Sodium Channel Blockade}}, url = {{http://dx.doi.org/10.2967/jnumed.121.261977}}, doi = {{10.2967/jnumed.121.261977}}, volume = {{62}}, year = {{2021}}, }