Transcriptional response in normal mouse tissues after i.v. 211At administration - response related to absorbed dose, dose rate, and time

Abstract

BackgroundIn cancer radiotherapy, knowledge of normal tissue responses and toxicity risks is essential in order to deliver the highest possible absorbed dose to the tumor while maintaining normal tissue exposure at non-critical levels. However, few studies have investigated normal tissue responses in vivo after 211At administration. In order to identify molecular biomarkers of ionizing radiation exposure, we investigated genome-wide transcriptional responses to (very) low mean absorbed doses from 211At in normal mouse tissues.MethodsFemale BALB/c nude mice were intravenously injected with 1.7 kBq 211At and killed after 1 h, 6 h, or 7 days or injected with 105 or 7.5 kBq and killed after 1 and 6 h, respectively. Controls were mock-treated. Total RNA was extracted from tissue samples of kidney cortex and medulla, liver, lungs, and spleen and subjected to microarray analysis. Enriched biological processes were categorized after cellular function based on Gene Ontology terms.ResultsResponses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function. Dose rate effects on transcript regulation were observed with both direct and inverse trends. In several tissues, Angptl4, Per1 and Per2, and Tsc22d3 showed consistent transcript regulation at all exposure conditions.ConclusionsThis study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after 211At administration. Transcript regulation of individual genes, as well as cellular responses inferred from enriched transcript data, may serve as biomarkers in vivo. These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0078-7) contains supplementary material, which is available to authorized users.

Microarray Studies on211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Nonthyroid Tissues

“…This follow-up study was performed on microarray data obtained from 4 experimental studies discussed elsewhere (21)(22)(23)(24). Briefly, 211 At was produced via the 209 Bi(a,2n) 211 At reaction at the Cyclotron and PET Unit at Rigshospitalet in Copenhagen, Denmark, and expressdelivered to Gothenburg, Sweden.…”

“…In the dose-range studies, responses were analyzed after 24 h after administration of 0.064, 0.64, 1.8, 14, or 42 kBq of 211 At (21,22). In the short-time studies, an activity of 1.7 kBq was administered and responses studied after 1 h, 6 h, or 7 d (23,24). The control group was mock-treated with physiologic saline and killed after 24 h. The administered activities were chosen to deliver a desired absorbed dose over a certain period to the thyroid.…”

“…Animal handling and preparation of tissue samples have been described previously (22). Tissue-specific absorbed dose was adapted from previously published work (21)(22)(23)(24); briefly, the absorbed dose was calculated using the MIRD formalism (26). All studies were approved by the Ethical Committee on Animal Experiments in Gothenburg, Sweden.…”

“…To discern between IR-and TH-induced responses, literature-based signature genes were compiled, and the microarray data (21)(22)(23)(24) were analyzed with regard to significantly regulated transcripts within respective signatures. The IR-associated gene signature was composed of 56 genes adapted from Snyder and Morgan (29) …”

Synthetic nanoparticles for delivery of radioisotopes and radiosensitizers in cancer therapy

“…In addition to β emitters, α emitters and Auger emitters also have been evaluated in cancer therapy due to their promising energy transfer properties. For example, 211 Astatine is a synthetic α emitter with a mean linear energy transfer value optimal for inducing DNA double-strand breaks (Langen et al 2015). Auger electrons (Kassis 2004), on the other hand, are low-energy electrons generated by the radioisotopes that decay by electron capture and/or internal conversion (e.g., 125 Iodine, 123 Iodine, and 77 Bromine).…”