Improved 223Ra Therapy with Combination Epithelial Sodium Channel Blockade

[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

Fears, Amanda (author)
Summer, Lucy (author)
Longtine, Mark (author)
Benabdallah, NadiaWashington University in St. Louis (author)
Riddle, Ryan C.Johns Hopkins University,Baltimore Veterans Administration Medical Center (author)
Ulmert, DavidLund University,Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Strålterapi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Radiation therapy,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,University of California, Los Angeles(Swepub:lu)klke-dul (author)
Michalski, Jeff M.Washington University in St. Louis (author)
Wahl, Richard L. (author)
Chesner, DeniseJohns Hopkins University School of Medicine (author)
Doucet, MicheleJohns Hopkins University School of Medicine (author)
Zachos, Nicholas C.Johns Hopkins University School of Medicine (author)
Simons, Brian W.Baylor College of Medicine (author)
Thorek, Daniel L.J.Washington University in St. Louis (author)
Washington University in St. LouisJohns Hopkins University (creator_code:org_t)

In:Journal of Nuclear Medicine: Society of Nuclear Medicine62:12, s. 1751-17580161-55052159-662X

By the author/editor: Abou, Diane S.; Fears, Amanda; Summer, Lucy; Longtine, Mark; Benabdallah, Nad ...; Riddle, Ryan C.; show more...; Ulmert, David; Michalski, Jeff ...; Wahl, Richard L.; Chesner, Denise; Doucet, Michele; Zachos, Nicholas ...; Simons, Brian W.; Thorek, Daniel L ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Urology and Neph ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Radiology Nuclea ...

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