Cellular Response to Exponentially Increasing and Decreasing Dose Rates

Objectives The treatment of cancer using targeted radionuclide therapy is of interest to the radiation oncology field due to its potential for killing tumor cells while minimizing dose-limiting toxicities to normal tissue. Ionizing radiation emitted by targeted radionuclide therapy delivers radiation absorbed doses over protracted periods of time with continuously varying dose rates. As RIT becomes a more prominent part of cancer therapy, accurate models for predicting biologically effective dose (BED) or equieffective dose (EQD2_α/β) will become essential. This study examines the radiobiological impact of the dose rate increase half-time during the uptake phase of the radiopharmaceutical.

Methods V79 Chinese hamster lung fibroblasts were irradiated acutely or with continuously varying dose rates with ¹³⁷Cs γ-rays for 168 h. The following dose rate patterns were delivered: acute, monoexponentially decreasing (T_d=64 h), and exponentially increasing and decreasing with different increase half-times (T_i=2 h and T_d=64 h, T_i=8 h and T_d=64 h, T_i=24 h and T_d=64 h). Cell survival assays were carried out and surviving fractions were calculated.

Results Data obtained from survival assays demonstrated that increasing T_i leads to increasing cell sparing. Conventional dose response models (BED and EQD2_α/β) were not able to fit the cell survival data; they underestimate both BED and EQD2_α/β at high dose rates and overestimate both at low dose rates. Cell cycle analysis suggested that differences in radiosensitivity cannot be attributed to redistribution. Accordingly, the expressions for BED and EQD2_α/β were modified empirically with an adaptive response function that fit the experimental data more accurately.

Conclusions Our experimental data demonstrates a marked increase in cell survival when the dose rate increase half-time is increased, thereby suggesting an adaptive response arising as a consequence of this phase of the irradiation. We have modified conventional radiobiological models to account for this phenomenon.