The cell cycle effects, alteration in radiation response, and inherent cytotoxicity of the
metal chelators mimosine,
desferrioxamine (DFO), N,N'-bis(o-hydroxybenzyl)-
ethylenediamine-N,N'-diacetic
acid (
HBED), and
deferiprone (L1) were studied in exponentially growing Chinese hamster V79 cells. Incubation of cells with 200-1000 microM
mimosine for 12 h reduced clonogenic survival to 50-60%, while incubation for 24 h reduced survival further to 0.5%.
Mimosine treatment resulted in cell cycle blocks at the G(1)/S-phase border and in S phase. Pulse labeling with
5-bromodeoxyuridine indicated that the S-phase cells ceased to actively replicate
DNA after only 2 h of
mimosine treatment and were unable to replicate
DNA for extended periods. Treatment of V79 cells with 600 microM
mimosine for 12 h resulted in radiosensitization, yielding a sensitizer enhancement ratio (SER) of 2.7 +/- 0.3 at the 10% survival level. To study the kinetics of the sensitization, V79 cells were incubated with
mimosine for various times up to 12 h and irradiated with a single 10-Gy dose of X rays. It was found that the radiosensitization increased continually up to 8 h (from a 3- to a 100-fold difference in survival) and then reached a plateau after 8 h.
Mimosine also equally radiosensitized human
lung cancer cells having either a normal or mutated TP53 gene, suggesting a TP53-independent mechanism. To test whether
iron binding by
mimosine was responsible for the observed radiosensitization, additional experiments were performed using the
iron chelators DFO,
HBED and L1. V79 cells treated with 500 microM of these agents for 8 h followed by various doses of X rays gave SERs similar to that for
mimosine (2.0-2.7). These studies indicate that
metal chelators are potent radiosensitizers in V79 and human cells. Importantly, when the DFO was preloaded together with Fe(3+) [Fe(III)-DFO], the
radiosensitizing effect was lost. These preliminary findings warrant further studies for the possible application of
metal chelators as
radiation sensitizers in radiation oncology.