Experimental concepts for toxicity prevention and tissue restoration after central nervous system irradiation

Abstract

Several experimental strategies of radiation-induced central nervous system toxicity prevention have recently resulted in encouraging data. The present review summarizes the background for this research and the treatment results. It extends to the perspectives of tissue regeneration strategies, based for example on stem and progenitor cells. Preliminary data suggest a scenario with individually tailored strategies where patients with certain types of comorbidity, resulting in impaired regeneration reserve capacity, might be considered for toxicity prevention, while others might be "salvaged" by delayed interventions that circumvent the problem of normal tissue specificity. Given the complexity of radiation-induced changes, single target interventions might not suffice. Future interventions might vary with patient age, elapsed time from radiotherapy and toxicity type. Potential components include several drugs that interact with neurodegeneration, cell transplantation (into the CNS itself, the blood stream, or both) and creation of reparative signals and a permissive microenvironment, e.g., for cell homing. Without manipulation of the stem cell niche either by cell transfection or addition of appropriate chemokines and growth factors and by providing normal perfusion of the affected region, durable success of such cell-based approaches is hard to imagine.

Figure 1

Schematic concept of the time course of radiation-induced reactions in cancer patients treated with ionizing radiation via portals exposing some part of the central nervous system (CNS). The tumor is expected to become eradicated within a few weeks. The severity and latency of CNS reactions are dose-dependent. Three different levels are shown. Acute CNS reactions often remain below the level of clinical detection and resolve early. A second wave of so-called late reactions might develop after several months or years and after higher radiation doses. The upper curve with or without additional comorbidity shows how certain factors might influence damage progression or make intervention more difficult. The dotted line below the threshold level represents succesful therapeutic intervention, which was started at the time indicated by the arrow.

Figure 2

Growth factors influence several steps of neurogenesis. NSC: neural stem cell, NPC: neural progenitor cell, GPC: glial progenitor cell, FGF-2: basic fibroblast growth factor, EGF: epidermal growth factor, CNTF: ciliary neurotrophic factor, EPO: erythropoietin, PDGF: platelet-derived growth factor, IGF-1: insulin-like growth factor-1, BMP-2: bone morphogenetic protein-2, BDNF: brain-derived neurotrophic factor, T3: thyroid hormone