Molecular markers of radiation-related normal tissue toxicity

Abstract

Over the past five decades, those interested in markers of radiation effect have focused primarily on tumor response. More recently, however, the view has broadened to include irradiated normal tissues-markers that predict unusual risk of side-effects, prognosticate during the prodromal and therapeutic phases, diagnose a particular toxicity as radiation-related, and, in the case of bioterror, allow for tissue-specific biodosimetry. Currently, there are few clinically useful radiation-related biomarkers. Notably, levels of some hormones such as thyroid-stimulating hormone (TSH) have been used successfully as markers of dysfunction, indicative of the need for replacement therapy, and for prevention of cancers. The most promising macromolecular markers are cytokines: TGFbeta, IL-1, IL-6, and TNFalpha being lead molecules in this class as both markers and targets for therapy. Genomics and proteomics are still in nascent stages and are actively being studied and developed.

Figure 1

Different physiological processes, many of which are not specifically related to the direct instantaneous damage caused by radiation, progress over time to create normal tissue toxicity. Markers are needed at all stages of the process including markers for both the direct effects of the radiation and the indirect and thus potentially reversible radiation effects.

Figure 2

Cytogenetic preparation of irradiated lymphocytes (3 Gy) from a female subject. The radiation produced a dicentric chromosome (#12, grey horizontal arrow) by the translocation of chromosome #4 onto #12, also forming an acentric fragment (black vertical arrow).

Figure 3

TGFβ1 is among the most studied circulating biomarkers of radiation fibrosis, and there is a strong association between circulating levels of this cytokine and fibrosis in irradiated mice and in human disease. Panels a-d show mice irradiated to the hind limb with 40 Gy at 4 weeks post-exposure. Note the depilation of the C57BL/6[+/+] and Balb/C mice compared to the relatively healthy appearance of the C3H/HeN and heterozygous knockout TGFB1[+/-] mice. The C57Bl/6 mouse is known to have a high propensity for radiation fibrosis and the C3H/HeN a low, while the Balb/C is intermediately fibrosing following irradiation. Heterozygous knockout TGFβ1 mice are phenotypically normal, but have a life-long low level of circulating TGFβ1 and a similarly low level of depilation, muscle wasting, and scarring following irradiation. The histogram (panel e) indicates the naturally occurring plasma levels of TGFβ1 (no radiation given) for these 4 mouse strains as a function of age.