Cargando…

Improved (223)Ra Therapy with Combination Epithelial Sodium Channel Blockade

[(223)Ra]RaCl(2) is the first approved α-particle–emitting therapy and is indicated for treatment of bone metastatic castration-resistant prostate cancer. Approximately half the dose is absorbed into the gastrointestinal tract within minutes of administration, limiting disease-site uptake and contri...

Descripción completa

Detalles Bibliográficos
Autores principales: Abou, Diane S., Fears, Amanda, Summer, Lucy, Longtine, Mark, Benabdallah, Nadia, Riddle, Ryan C., Ulmert, David, Michalski, Jeff M., Wahl, Richard L., Chesner, Denise, Doucet, Michele, Zachos, Nicholas C., Simons, Brian W., Thorek, Daniel L.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society of Nuclear Medicine 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612198/
https://www.ncbi.nlm.nih.gov/pubmed/33837069
http://dx.doi.org/10.2967/jnumed.121.261977
Descripción
Sumario:[(223)Ra]RaCl(2) is the first approved α-particle–emitting therapy and is indicated for treatment of bone metastatic 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) as in vitro models of the functional gastrointestinal epithelium, we found that amiloride (epithelial sodium ion channel blocker) and NS-1619 (K(+) channel activator) presented significant effects in (223)Ra membranal transport. Radioactive drug distribution was evaluated for lead combinations in vivo and in osteosarcoma and prostate cancer models. Results: Amiloride shifted (223)Ra uptake in vivo from the gut and nearly doubled the uptake at sites of bone remodeling. Bone tumor growth inhibition with the combination as measured by bioluminescent imaging and radiography was significantly greater than that with single agents alone, and the combination resulted in no weight loss. Conclusion: This combination of approved agents may readily be implemented as a clinical approach to improve the outcomes of bone-metastatic cancer patients with the benefit of ameliorated tolerability.