Introduction to radiobiology of targeted radionuclide therapy

Abstract

During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRTs) are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT) and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors, which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure, and low absorbed dose rate) differ from those of conventional EBRT (homogeneous irradiation, short exposure, and high absorbed dose rate), and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose-effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related) and non-targeted effects (assumed to be non-dose-related) of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main challenges of TRT in the future.

Keywords: bystander effects; radiobiology; radioimmunotherapy; targeted radionuclide therapy.

Figure 1

Targeted and non-targeted biological effects in conventional external beam radiotherapy. Targeted effects are caused by one or more particles traversing irradiated cells and can be divided in DNA and non-DNA-centered effects. Non-targeted effects describes the effects observed in cells that have not been directly traversed by particles but that are close to irradiated cells, as well as long-distance effects. DNA, mitochondria, and the cell membrane are the main sensitive targets of radiation. Following targeted and non-targeted effects, cells can survive (lesions are effectively repaired), they can die (lesions are not repaired) or they can be transformed. The dose–effect relationship of targeted effects is commonly fitted by linear or linear-quadratic models. A saturation of the response to non-targeted effects has been described. For more details, see the main text.

Figure 2

Targeted and non-targeted effects in targeted radionuclide therapy. Targeted effects are caused by one or more particles crossing irradiated cells and can be due to self-irradiation and cross-fire irradiation. Non-targeted effects include effects observed in cells close to irradiated cells and also long-distance effects. The nature of the dose–effect relationship resulting from targeted and non-targeted effects needs to be determined. For more details, see the main text.

Figure 3

Comparison of conventional external beam radiotherapy and targeted radionuclide therapy.