title: Transcript Analysis for Internal Biodosimetry Using Peripheral Blood from Neuroblastoma Patients Treated with (131)I-mIBG, a Targeted Radionuclide.
abstract: Calculating internal dose from therapeutic radionuclides currently relies on estimates made from multiple radiation exposure measurements, converted to absorbed dose in specific organs using the Medical Internal Radiation Dose (MIRD) schema. As an alternative biodosimetric approach, we utilized gene expression analysis of whole blood from patients receiving targeted radiotherapy. Collected blood from patients with relapsed or refractory neuroblastoma who received (131)I-labeled metaiodobenzylguanidine ((131)I-mIBG) at the University of California San Francisco (UCSF) was used to compare calculated internal dose with the modulation of chosen gene expression. A total of 40 patients, median age 9 years, had blood drawn at baseline, 72 and 96 h after (131)I-mIBG infusion. Whole-body absorbed dose was calculated for each patient based on the cumulated activity determined from injected mIBG activity and patient-specific time-activity curves combined with (131)I whole-body S factors. We then assessed transcripts that were the most significant for describing the mixed therapeutic treatments over time using real-time polymerase chain reaction (RT-PCR). Modulation was evaluated statistically using multiple regression analysis for data at 0, 72 and 96 h. A total of 10 genes were analyzed across 40 patients: CDKN1A; FDXR; GADD45A; BCLXL; STAT5B; BAX; BCL2; DDB2; XPC; and MDM2. Six genes were significantly modulated upon exposure to (131)I-mIBG at 72 h, as well as at 96 h. Four genes varied significantly with absorbed dose when controlling for time. A gene expression biodosimetry model was developed to predict absorbed dose based on modulation of gene transcripts within whole blood. Three transcripts explained over 98% of the variance in the modulation of gene expression over the 96 h (CDKN1A, BAX and DDB2). To our knowledge, this is a novel study, which uses whole blood collected from patients treated with a radiopharmaceutical, to characterize biomarkers that may be useful for biodosimetry. Our data indicate that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good early indicators of internal exposure. However, for internal sources of radiation, the biokinetics and physical decay of the radionuclide strongly influence the gene expression.
authors.affiliation: a   School of Health Sciences, Purdue University, West Lafayette, Indiana 47907;
authors.forename: David A
authors.initials: DA
authors.lastname: Edmondson
authors.affiliation: b   Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco California 94143;
authors.forename: Erin E
authors.initials: EE
authors.lastname: Karski
authors.affiliation: c   Lawrence Livermore National Laboratory, Livermore, California 94550;
authors.forename: Ayano
authors.initials: A
authors.lastname: Kohlgruber
authors.affiliation: c   Lawrence Livermore National Laboratory, Livermore, California 94550;
authors.forename: Harsha
authors.initials: H
authors.lastname: Koneru
authors.affiliation: b   Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco California 94143;
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.affiliation: b   Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco California 94143;
authors.forename: Shelly
authors.initials: S
authors.lastname: Allen
authors.affiliation: c   Lawrence Livermore National Laboratory, Livermore, California 94550;
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hartmann
authors.affiliation: d   Center for Biostatistics, Houston Methodist Research Institute. Houston, Texas 77030; and.
authors.forename: Leif E
authors.initials: LE
authors.lastname: Peterson
authors.affiliation: b   Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco California 94143;
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.affiliation: c   Lawrence Livermore National Laboratory, Livermore, California 94550;|e   Department of Radiation Oncology, University of California Davis, School of Medicine, Davis, California 95817.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Coleman
mesh_terms: D019797:3-Iodobenzylguanidine / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000097:blood* / Q000235:genetics / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011874:Radiometry / Q000379:methods*; D013997:Time Factors; D059467:Transcriptome / Q000528:radiation effects; D014916:Whole-Body Irradiation; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D019797:3-Iodobenzylguanidine