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dc.contributor.authorDondossola, Eleonora
dc.contributor.authorCasarin, Stefano
dc.contributor.authorPaindelli, Claudia
dc.contributor.authorDe-Juan-Pardo, Elena M
dc.contributor.authorHutmacher, Dietmar W
dc.contributor.authorLogothetis, Christopher J
dc.contributor.authorFriedl, Peter
dc.date.accessioned2019-07-15T01:33:19Z
dc.date.available2019-07-15T01:33:19Z
dc.date.issued2019
dc.identifier.issn0027-8874
dc.identifier.doi10.1093/jnci/djz007
dc.identifier.urihttp://hdl.handle.net/10072/386388
dc.description.abstractBackground: Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (∼100 µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Rad-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome. Methods: We tested Rad-223 overall response by PC3 and C4–2B human PCa cell lines in mouse bones (n = 5–18 tibiae per group). Rad-223 efficacy at subcellular resolution was determined by intravital microscopy analysis of dual-color fluorescent PC3 cells (n = 3–4 mice per group) in tissue-engineered bone constructs. In vivo data were fed into an in silico model to predict Rad-223 effectiveness in lesions of different sizes (1–27, 306 initial cells; n = 10–100 simulations) and the predictions validated in vivo by treating PCa tumors of varying sizes in bones (n = 10–14 tibiae per group). Statistical tests were performed by two-sided Student t test or by one-way ANOVA followed by Tukey’s post-hoc test. Results: Rad-223 (385 kBq/kg) delayed the growth (means [SD]; comparison with control-treated mice) of PC3 (6.7 × 105 [4.2 × 105] vs 2.8 × 106 [2.2 × 106], P = .01) and C4–2B tumors in bone (7.7 × 105 [4.0 × 105] vs 3.5 × 106 [1.3 × 106], P < .001). Cancer cell lethality in response to Rad-223 (385 kBq/kg) was profound but zonally confined along the bone interface compared with the more distant tumor core, which remained unperturbed (day 4; 13.1 [2.3%] apoptotic cells, 0–100 µm distance from bone vs 3.6 [0.2%], >300 µm distance; P = .01). In silico simulations predicted greater efficacy of Rad-223 on single-cell lesions (eradication rate: 88.0%) and minimal effects on larger tumors (no eradication, 16.2% growth reduction in tumors of 27 306 cells), as further confirmed in vivo for PC3 and C4–2B tumors. Conclusions: Micro-tumors showed severe growth delay or eradication in response to Rad-223, whereas macro-tumors persisted and expanded. The relative inefficacy in controlling large tumors points to application of Rad-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherOxford University Press
dc.relation.ispartoflocationUnited States
dc.relation.ispartofpagefrom1
dc.relation.ispartofpageto9
dc.relation.ispartofjournalJournal of the National Cancer Institute
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode1112
dc.titleRadium 223-mediated zonal cytotoxicity of prostate cancer in bone
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.description.notepublicThis publication has been entered into Griffith Research Online as an Advanced Online Version.
gro.hasfulltextNo Full Text
gro.griffith.authorHutmacher, Dietmar W.


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