title: Isolating effects of microscopic nonuniform distributions of (131)I on labeled and unlabeled cells.
abstract: Radiopharmaceuticals are generally distributed nonuniformly in tissue. At the microscopic level, only a fraction of the cells in tissue are labeled. Consequently, the labeled cells receive an absorbed dose from radioactivity within the cell (self-dose) as well as an absorbed dose from radioactivity in surrounding cells (cross-dose). On the other hand, unlabeled cells only receive a cross-dose. This work uses a novel approach to examine the lethal effects of microscopic nonuniformities of (131)I individually on the labeled and unlabeled cells.
  
  
  METHODS
  A multicellular tissue model was used to investigate the lethality of microscopic nonuniform distributions of (131)I. Mammalian cells (V79) were dyed with CFDA-SE (carboxy fluorescein diacetate succinimidyl ester) and labeled with (131)I-iododeoxyuridine ((131)IdU). The dyed labeled cells were then mixed with equal numbers of unlabeled cells, and 3-dimensional tissue constructs (4 x 10(6) cells) were formed by centrifugation in a small tube. This resulted in a uniform distribution of (131)I at the macroscopic level but nonuniform distribution at the multicellular level, wherein 50% of the cells were labeled. The multicellular clusters were maintained at 10.5 degrees C for 72 h to allow (131)I decays to accumulate. The clusters were then dismantled and the labeled (dyed) and unlabeled (undyed) cells were separately seeded for colony formation using a fluorescence-activated cell sorter.
  
  
  RESULTS
  The unlabeled cells, which received only a cross-dose, exhibited a mean lethal dose D(37) of 4.0 +/- 0.3 Gy. In contrast, the labeled cells received both a self-dose and a cross-dose. Isolating the effects of the self-dose resulted in a D(37) of 1.2 +/- 0.3 Gy, which was about 3.3 times more toxic per unit dose than the cross-dose. The reason for these differences appears to be primarily related to the higher relative biological effectiveness of the self-dose delivered by (131)IdU compared with the cross-dose. Theoretical modeling of the killing of labeled and unlabeled cells was achieved by considering the cellular self-doses and cross-doses.
  
  
  CONCLUSIONS
  Cellular self-doses and cross-doses play an important role in determining the biological response of tissue to microscopic nonuniform distributions of (131)I. Prediction of the biological response requires that both self-doses and cross-doses be considered along with their relative lethality per unit dose.
authors.affiliation: Department of Radiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Prasad V S V
authors.initials: PV
authors.lastname: Neti
authors.forename: Roger W
authors.initials: RW
authors.lastname: Howell
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000528:radiation effects; D002469:Cell Separation / Q000379:methods; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000145:classification / Q000378:metabolism* / Q000528:radiation effects*; D005434:Flow Cytometry / Q000379:methods; D007457:Iodine Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008168:Lung / Q000378:metabolism / Q000528:radiation effects; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals