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Isolating Effects of Microscopic Nonuniform Distributions of ¹³¹I on Labeled and Unlabeled Cells

¹ Division of Radiation Research, Department of Radiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey

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 ¹³¹I individually on the labeled and unlabeled cells. Methods: A multicellular tissue model was used to investigate the lethality of microscopic nonuniform distributions of ¹³¹I. Mammalian cells (V79) were dyed with CFDA-SE (carboxy fluorescein diacetate succinimidyl ester) and labeled with ¹³¹I-iododeoxyuridine (¹³¹IdU). The dyed labeled cells were then mixed with equal numbers of unlabeled cells, and 3-dimensional tissue constructs (4 x 10⁶ cells) were formed by centrifugation in a small tube. This resulted in a uniform distribution of ¹³¹I 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°C for 72 h to allow ¹³¹I 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 D₃₇ 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 D₃₇ 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 ¹³¹IdU 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. Conclusion: Cellular self-doses and cross-doses play an important role in determining the biological response of tissue to microscopic nonuniform distributions of ¹³¹I. Prediction of the biological response requires that both self-doses and cross-doses be considered along with their relative lethality per unit dose.

Key Words: ¹³¹I • iodine-131 • iododeoxyuridine • cellular dosimetry • multicellular cluster • V79 cells • survival • ionizing radiation • ß-particles • radiation effects • adverse effects • therapeutic use • fluorescence-activated cell sorting

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