An approach to assessing the contribution of the high LET effect in strategies for Auger endoradiotherapy

Abstract

Purpose: The interest in exploiting Auger emitters in cancer therapy stems from their high linear energy transfer (LET) – type radiation damage. However, the design of Auger-emitter labelled vehicles, that target the Auger cascade specifically to tumour cells, is challenging, especially to bring the decay event close enough to DNA to inflict high LET– type damage in DNA. Here we suggest a possible approach to evaluate tumour-targeting Auger-labelled conjugates by assessing the impact of a radioprotector known to be effective in protecting low LET radiation, but ineffective in protecting against high LET-type radiation. However, the efficacy of the radioprotector is not known in the context of irradiation by low energy electrons from randomly distributed Auger emitters. Given some similarity between the energy spectrum of Auger electrons and that of secondary electrons from soft X-rays, we report the results of radioprotection experiments with 25 kVp X-rays. Materials and methods: Clonogenic survival curves for cultured human keratinocytes were established for three different irradiation conditions: 137Cs γ-rays, 25 keV X-rays (effective energy 15.5 keV) and 320 kVp X-rays, and the effect of including a new methylproamine analogue, denoted “2PH”, before and during irradiation, was investigated. Results: The extent of radioprotection by 2PH was essentially the same for all radiation conditions, although RBE was higher (about 1.7) for soft X-rays. This suggests that the effects of randomly distributed Auger emitters will be largely subject to radioprotection. Conclusions: It is reasonable to expect that use of methylproamine analogues will help to ascertain the relative contributions of the high-LET effects (not protected), compared to other components, including bystander effects, that are subject to radioprotection. This could be a useful tool in evaluating Auger endoradiotherapy strategies.