Isolating effects of microscopic nonuniform distributions of ¹³¹I on labeled and unlabeled cells

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 × 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 10.5̊C 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 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 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.