Modeling Multicellular Response to Nonuniform Distributions of Radioactivity: Differences in Cellular Response to Self-Dose and Cross-Dose

Abstract

Radiopharmaceuticals are distributed nonuniformly in tissue. While distributions of radioactivity often appear uniform at the organ level, in fact, microscopic examination reveals that only a fraction of the cells in tissue are labeled. Labeled cells and unlabeled cells often receive different absorbed doses depending on the extent of the nonuniformity and the characteristics of the emitted radiations. The labeled cells receive an absorbed dose from radioactivity within the cell (self-dose) as well as an absorbed dose from radioactivity in surrounding labeled cells (cross-dose). Unlabeled cells receive only a crossdose. In recent communications, a multicellular cluster model was used to investigate the lethality of microscopic nonuniform distributions of 131 I iododeoxyuridine ( 131 IdU). For a given mean absorbed dose to the tissue, the dose response depended on the percentage of cells that were labeled. Specifically, when 1, 10 and 100% of the cells were labeled, a D 37 of 6.4, 5.7 and 4.5 Gy, respectively, was observed. The reason for these differences was recently traced to differences in the cellular response to the self-and cross-doses delivered by 131 IdU. Systematic isolation of the effects of self-dose resulted in a D 37 of 1.2 ± 0.3 Gy. The cross-dose component yielded a D 37 of 6.4 ± 0.5 Gy. In the present work, the overall survival of multicellular clusters containing 1, 10 and 100% labeled cells is modeled using a semi-empirical approach that uses the mean lethal self-and crossdoses and the fraction of cells labeled. There is excellent agreement between the theoretical model and the experimental data when the surviving fraction is greater than 1%. Therefore, when the distribution of 131 I in tissue is nonuniform at the microscopic level, and the cellular response to selfand cross-doses differs, multicellular dosimetry can be used successfully to predict biological response, whereas the mean absorbed dose fails in this regard.

Challenges and progress in predicting biological responses to incorporated radioactivity

“…131 I). Initial modeling of the killing of labeled and unlabeled cells was achieved by considering the cellular self-and cross-doses and the fraction of cells labeled (39).…”

“…This approach was used to model the observed responses for 210 Po-citrate (not shown) and 131 IdU (39). The model afforded an excellent fit to the first two logs of killing in all three labeling cases (1%, 10%, 100%).…”

Survival of tumor and normal cells upon targeting with electron‐emitting radionuclides

“…18,19 In previous work, paired theoretical and experimental multicellular dose-response models were created to improve our understanding of, and modeling capabilities for, nonuniform distributions of radioactivity. 8,21,22 Three-dimensional (3D) models of cell clusters have been developed for experimental as well as theoretical studies. 8,22 More recently, considerable effort has been devoted towards developing a 3D tissue culture model that more closely simulates human tissue in vivo.…”

“…8,21,22 Three-dimensional (3D) models of cell clusters have been developed for experimental as well as theoretical studies. 8,22 More recently, considerable effort has been devoted towards developing a 3D tissue culture model that more closely simulates human tissue in vivo. This 3D tissue culture model uses human cells grown in a Cytomatrix TM carbon scaffold and has been used to examine the impact of nonuniform distributions of radioactivity in both tumor and normal human tissues.…”

Cell-Level Dosimetry and Biologic Response Modeling of Heterogeneously Distributed Radionuclides: A Step Forward

“…Novel features of this cell culture model and dosimetric analysis include a structurally heterogeneous, more realistic milieu comprising water-equivalent cells, a Cytomatrix carbon scaffold (mass density, 2 gÁcm 23 ) in the form of irregular ligaments, and a water-filled extracellular space; empirically validated modeling of the differential radiobiologic effectiveness between cell selfand cross-doses (corresponding to mean lethal doses D 37 of 400 and 120 cGy, respectively, for low-linearenergy-transfer radiations) (21-23); and a lognormal distribution of activity among cells, with quantitative assessment of the effect on overall survival of varying degrees of nonuniformity of the activity per cell (i.e., corresponding to values of 0.6, 1.0, and 2.0 of the so-called shape parameter s of the lognormal probability density function) (22,24,25). On the basis of the calculated cell nuclei doses and previously published models of cell killing, survival curves were derived and characterized in relation to the electron energy and the nonuniformity of the activity distribution.…”