Activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARP) has been implicated in the process of recovery from radiation induced cell injury. Consequently, inhibitors of PARP or cells deficient from PARP exhibit enhancements in their radiation sensitivity. The principle of this radiosensitizing effect of PARP inhibition can be exploited for the development of novel radiosensitizing agents for cancer therapy. The applicants are developing a series of novel, proprietary PARP inhibitors, with a high potency, good water-solubility and optimal cell penetration characteristics. The goal of the present application, supported by preliminary data, is to confirm that the applicants' proprietary, novel PARP inhibitors act as potent radiosensitizers in vivo, and to select a lead candidate for further preclinical development (i.e. toxicity and safety studies). The results of the present application will permit application for Phase 2 funding to support: completion of pre-clinical pharmaceutical testing (additional advanced toxicity determinations, pathology, stability, pharmacokinetics), preparation of investigational drug application to the FDA, and a Phase I and II clinical trials.
The annual anticipated revenues for an effective therapeutic to safely enhance radiation therapy is over $100 million in the US alone.
| Brock, William A; Milas, Luka; Bergh, Sherry et al. (2004) Radiosensitization of human and rodent cell lines by INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase. Cancer Lett 205:155-60 |
