What is the Role of the Bystander Response in Radionuclide Therapies?

Abstract

Radionuclide therapy for cancer is undergoing a renaissance, with a wide range of radionuclide and clinical delivery systems currently under investigation. Dosimetry at the cellular and sub-cellular level is complex with inhomogeneity and incomplete targeting of all cells such that some tumor cells will receive little or no direct radiation energy. There is now sufficient preclinical evidence of a Bystander response which can modulate the biology of these un-irradiated cells with current research demonstrating both protective and inhibitory responses. Dependence upon fraction of irradiated cells has also been found and the presence of functional gap junctions appears to be import for several Bystander responses. The selection of either high or low LET radionuclides may be critical. While low LET radionuclides appear to have a Bystander response proportional to dose, the dose-response from high LET radionuclides are more complex. In media transfer experiments a “U” shaped response curve has been demonstrated for high LET treatments. However this “U” shaped response has not been seen with co-culture experiments and its relevance remains uncertain. For high LET treatments there is a suggestion that dose rate effects may also be important with inhibitory effects noted with 125I labelling study and a stimulatory seen with 123I labelling in one study.

MIRD Pamphlet No. 25: MIRDcell V2.0 Software Tool for Dosimetric Analysis of Biologic Response of Multicellular Populations

“…Bystander, cohort, and abscopal effects are not explicitly modeled in this program (52). They can be of considerable importance in the context of targeted radionuclide therapy (53) and, more specifically, in the context of the algorithms used in MIRDcell V2.0 when small fractions of cells are labeled with a-particle emitters (31). Therefore, users of MIRDcell V2.0 should be cognizant that radiation-induced bystander effects might alter the results.…”

Radiation-induced glioblastoma signaling cascade regulates viability, apoptosis and differentiation of neural stem cells (NSC)

“…However, demonstration of bystander effects in non-targeted cells in diverse human cell systems raises a serious health concern [18, 32]. Understanding the intrinsic cellular communication between cancer and non-cancer cells, especially after radiation exposure, is highly desirable for development of strategies to either minimize or prevent the harmful radiation effects on normal stem cells, which are critical for tissue homeostasis.…”

223Ra and other bone-targeting radiopharmaceuticals—the translation of radiation biology into clinical practice

“…The bystander effect with regard to radionuclides specifically has been comprehensively reviewed by Brady et al 13 who cite evidence of the phenomenon both in vitro and in vivo. In experiments by Bishayee et al, 14 Chinese hamster cells were labelled with tritiated thymidine and mixed with unlabelled cells to form clusters.…”