title: The cytokinesis-block micronucleus assay as a biological dosimeter for targeted alpha therapy.
abstract: Ionizing radiation causes structural chromosomal aberrations, a proportion of which give rise to chromosome fragments without spindle attachment organelles. When a cell divides, some of these fragments are excluded from the main daughter nuclei and form small nuclei within the cytoplasm. The cytokinesis-block micronucleus assay allows these micronuclei (MN) to be counted, providing an in situ biological dosimeter. In this study, we evaluated the micronucleus frequency in peripheral blood lymphocytes after in vitro incubation with the alpha conjugates (213)BiI(3) and (213)Bi-9.2.27 (AIC). Lymphocytes were inoculated in vitro AIC for 3 h. Further, we report the first MN measurements in melanoma patients after targeted alpha therapy (TAT) with (213)Bi-9.2.27. Patients were injected with 260-360 MBq of AIC, and blood samples taken at 3 h, 2 weeks and 4 weeks post-treatment. Absorbed dose (MIRD) and effective total body dose (PED) were calculated. The MN frequency in lymphocytes was similar for equal in vitro incubation activities of (213)BiI(3) and (213)Bi-9.2.27 (P=0.5), indicating that there is no selective targeting of lymphocytes by the alpha conjugates. After inoculation with 10-1200 kBq mL-1 of AIC, there was a substantial activity-related increase in MN. The number of MN in the blood of treated patients peaked at 3 h post-TAT, slowly returning to baseline levels by 4 weeks. The mean photon equivalent dose (PED) is 0.43 Gy (SD 0.15) and the mean MIRD calculated absorbed dose is 0.11 Gy (SD 0.03), giving an RBE=4+/-0.4 for this study.
authors.affiliation: Centre for Experimental Radiation Oncology, Cancer Care Centre, St George Hospital, Gray St, 2217 Kogarah, Australia.
authors.forename: Emma Y
authors.initials: EY
authors.lastname: Song
authors.forename: Syed M A
authors.initials: SM
authors.lastname: Rizvi
authors.forename: Chang F
authors.initials: CF
authors.lastname: Qu
authors.forename: Chand
authors.initials: C
authors.lastname: Raja
authors.forename: Johnson
authors.initials: J
authors.lastname: Yuen
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Christos
authors.initials: C
authors.lastname: Apostolidis
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Allen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000512:Alpha Particles / Q000627:therapeutic use; D001681:Biological Assay / Q000379:methods*; D048749:Cytokinesis / Q000528:radiation effects*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000166:cytology* / Q000528:radiation effects*; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D015162:Micronucleus Tests / Q000379:methods*; D008875:Middle Aged; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods*; D011878:Radiotherapy / Q000379:methods*; D012062:Relative Biological Effectiveness