Low-dose hyper-radiosensitivity model for 131I radioimmunotherapy of non-Hodgkin’s lymphoma

Objectives Radiation-induced DNA damage produces arrest in the G2/M phase of the cell cycle, allowing increased time for cells to undergo apoptosis. In the inverse dose-rate effect at low dose rates, the cells are more sensitive to radiation than at equivalent doses delivered at high dose rates. These phenomena are described by the low-dose Hyper-Radiosensitivity (HRS) model. HRS may help explain some of the dependence on radio-sensitivity found using the standard Bio-Effect model.

Methods Least square fits for the standard Bio-Effect Model, applied to tumor shrinkage data for 131I-Tositumomab therapy, yield an excellent correlation for tumor shrinkage with E (Equivalent Biological Effect), illustrating an excellent fit to the data. The fit parameter with the highest correlation to tumor shrinkage is radiation sensitivity. Model parameters were changed so that the radio-sensitivity, cold effect and proliferation parameters depend on the accumulated dose from current therapy and intensity of prior therapy. The proliferation parameter also depends on a critical dose rate appropriate for the initiation of cell cycle arrest.

Results Modifications to the standard Bio-Effect Model to incorporate HRS are: Radiosensitvity (α) and cold effect sensitivity (λp) are dependent on dose (d) and proir insult (I): α=αr [1+(a-1) e^(-(d/dc +I/Ic ) )] where a~3 and λp = λps e^(-(d/dc +I/Ic ) ), where dc ~0.3 Gy. Cell cycle arrest implies the temporary suspension of proliferation: Tp = Tp0 [e^(Dr/Dr-crit)+(1-e^(Dr/Dr-crit))e^(-(d/dc +I/Ic ) )] , where Tp is the effective doubling time, Dr is dose rate in Gy/hr and Dr-crit is the critical dose rate at which proliferation is stopped. If one double strand break is created every ~0.025 Gy and repair half-life is ~1.5 hr, then the critical dose rate is Dr-crit = 0.017 Gy/hr.

Conclusions Success of the HRS modification will be judged based on the decreased range of fit parameter values.

Research Support NIH 2R01 EB00199