The ability of the radiomimetic anti-
tumor enediyne
C-1027 to induce
DNA inter-strand crosslinks (ICLs), in addition to the expected
DNA strand breaks, is unique among traditional
DNA targeted
cancer therapies. Importantly,
radiation therapy and most radiomimetic drugs have diminished effect in hypoxic environments due to decreased induction of
DNA strand breaks, which is an
oxygen requiring process. However, C-1027's induction of ICLs is enhanced under
hypoxia and it is actually more potent against hypoxic cells, overcoming this common
tumor resistance mechanism. In this study, an analog of
C-1027,
20'-deschloro-C-1027 was examined for its ability to induce
DNA ICLs under hypoxic conditions. Deschloro-induced ICLs were detected under hypoxic cell-free conditions, with a concomitant reduction in the induction of
DNA strand breaks. In cells deschloro behaved similarly, inducing cellular ICLs under hypoxic conditions with a reduction in DNA breaks. The cytotoxicity of deschloro treatment was similar in normoxic and hypoxic cells, suggesting that the ICL induction allows deschloro to retain its cytotoxic activity under
hypoxia. It appears that rational engineering of the
C-1027 family of radiomimetics holds promise toward overcoming the radioresistance associated with the hypoxic environment associated with solid
tumors.