The nuclear enzyme poly(ADP-ribose) polymerase (PARP) plays an important role in the repair of DNA strand breaks, including those induced by radiation, thus making it a potential target for radiosensitizers. INO-1001 is a novel and potent inhibitor of PARP. INO-1001 at a concentration of 0.05 μM resulted in approximately 50% inhibition of PARP activity in CHO cells after 30 minutes treatment. And concentrations of 1 μM or greater resulted in more than 95% inhibition of the enzyme. Exponentially growing CHO cells were treated with 10 μM INO-1001 starting 30 min. prior to irradiation. INO-1001 significantly sensitized CHO cells to radiation. The initial slope of the survival curve for drug treated and irradiated cultures was greater than radiation alone. The enhancement ratio (ER) at 10% survival was 1.6. A similar radiosensitizing effect was observed in a murine tumor cell line with an ER of 1.7. The fibroblasts were also sensitized by the drug treatment with an ER of 1.4[2]. Immediately after CCI (controlled cortical impact) or sham-injury mice received either INO-1001 (1.6 mg/kg) or vehicle via intracerebral injection (5 microl over 5 min) in a randomized fashion. Local treatment with INO-1001 preserved brain NAD+ levels 2 h after CCI. In the Morris water maze, treatment with INO-1001 reduced the latency to find the hidden platform and increased the time spent in the target quadrant versus vehicle after CCI[3].
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