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000306272 005__ 20251119101458.0
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000306272 1001_ $$aMichaeli, Or$$b0
000306272 245__ $$aAPR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy.
000306272 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2024
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000306272 520__ $$aRadiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.
000306272 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000306272 650_7 $$2NLM Chemicals$$aTumor Suppressor Protein p53
000306272 650_7 $$0Z41TGB4080$$2NLM Chemicals$$aeprenetapopt
000306272 650_7 $$2NLM Chemicals$$aRadiation-Sensitizing Agents
000306272 650_7 $$2NLM Chemicals$$aQuinuclidines
000306272 650_7 $$2NLM Chemicals$$aTP53 protein, human
000306272 650_2 $$2MeSH$$aAlpha Particles: therapeutic use
000306272 650_2 $$2MeSH$$aHumans
000306272 650_2 $$2MeSH$$aTumor Suppressor Protein p53: metabolism
000306272 650_2 $$2MeSH$$aTumor Suppressor Protein p53: genetics
000306272 650_2 $$2MeSH$$aAnimals
000306272 650_2 $$2MeSH$$aMice
000306272 650_2 $$2MeSH$$aRadiation-Sensitizing Agents: pharmacology
000306272 650_2 $$2MeSH$$aMutation
000306272 650_2 $$2MeSH$$aQuinuclidines: pharmacology
000306272 650_2 $$2MeSH$$aCell Line, Tumor
000306272 650_2 $$2MeSH$$aMice, Nude
000306272 650_2 $$2MeSH$$aXenograft Model Antitumor Assays
000306272 650_2 $$2MeSH$$aApoptosis: drug effects
000306272 650_2 $$2MeSH$$aApoptosis: radiation effects
000306272 650_2 $$2MeSH$$aNeoplasms: radiotherapy
000306272 650_2 $$2MeSH$$aNeoplasms: genetics
000306272 650_2 $$2MeSH$$aNeoplasms: pathology
000306272 7001_ $$00000-0003-2060-7742$$aLuz, Ishai$$b1
000306272 7001_ $$aVatarescu, Maayan$$b2
000306272 7001_ $$aManko, Tal$$b3
000306272 7001_ $$aWeizman, Noam$$b4
000306272 7001_ $$aKorotinsky, Yevgeniya$$b5
000306272 7001_ $$aTsitrina, Alexandra$$b6
000306272 7001_ $$aBraiman, Alex$$b7
000306272 7001_ $$aArazi, Lior$$b8
000306272 7001_ $$00000-0003-0853-3437$$aCooks, Tomer$$b9
000306272 773__ $$0PERI:(DE-600)2541626-1$$a10.1038/s41419-024-06830-3$$gVol. 15, no. 6, p. 426$$n6$$p426$$tCell death & disease$$v15$$x2041-4889$$y2024
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