1458

Exposure to ionizing and ultraviolet radiation induces cell death due to oxidative damage of cellular macromolecules. A toxic effect of ionizing radiation therapy causes oral mucositis while prolonged exposure to UV radiation leads to photodamage and potentially to skin cancer. Prevention/treatment of mucositis and UV-mediated skin damage are important unmet medical needs. A broad-spectrum cytoprotective agent would be very useful to protect normal cells from exposure to a wide variety of radiation. We have identified a highly stable, water soluble, novel cytoprotective agent, ADP-ribose (ADPR), that can protect cells in vitro from cytotoxic effects induced by a variety of agents including TNF-α, H2O2 and UV radiation. Cytoprotective activity was specific to ADPR when compared to other purine derivatives tested. Based on these cytoprotective and radioprotective activities, we evaluated its efficacy in a hamster radiation model of oral mucositis and in a mouse sunburn model. In the hamster cheek pouch model, ADPR was administered topically to the left cheek pouch for irradiation while the right cheek was used as a control. ADPR was applied in 0.25 ml water (vehicle) at various concentrations three times per day from day -1 to day 6 and every other day through day 20. Mucositis was induced by a single dose of 40.0 Gy x-ray irradiation on day 0, and the experiment was continued until day 28. Mucositis scoring was based on the WHO scoring standard. Our results indicate that ADPR at 50 μg/ml concentration showed a statistically significant improvement in the course of ulcerative mucositis. The ADPR treatment group had a 28% reduction (p = 0.002) in the number of days of ulceration compared to the control group. In the SKH-1 hairless mouse model of UV mediated sunburn, test areas (1 cm2 uncovered skin) were treated either with ADPR [3% (w/w) or 10% (w/w) ADPR in 1.5% Natrosol gel] or Natrosol control 2 hr prior to erythematogenic 1 MED (minimal erythema dose) solar exposure. Tissue samples were collected 24 hr after exposure and subjected to H&E staining. Sunburn cells were counted and expressed as a number of sunburn cells per linear cm of skin. The results indicate a 48% and a 68% reduction in sunburn damage by 3% and 10% ADPR treatment, respectively. Based on the pre-clinical results, ADPR appears to be an excellent candidate for the protection of tissues from either ionizing or UV radiation. The mechanism of action of ADPR is under investigation.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]