Cdk Inhibitors in Prevention of Radiation-Induced Salivary Gland Dysfunction

Objectives: Treatment of head and neck cancer with radiation often results in permanent loss of function in the salivary glands. This impaired function often leads patients to discontinue treatment due to incapacitating side effects. It has previously been shown that IGF-1 suppresses radiation-induced apoptosis by activating G2/M arrest through the cyclin-dependent kinase inhibitor, p21. In an effort to recapitulate the effects of IGF1, as well as enhance clinical translatability, small molecule therapeutics are being tested. Roscovitine, CYC202, and AT7519 are all cyclin-dependent kinase inhibitors that act to inhibit cell cycle progression and allow for DNA repair in damaged tissues. Methods: Mice are treated withone of the cyclin-dependent kinase inhibitors concurrently with head and neck irradiation. Markers of G2/M arrest, as well as physiological function are assessed at various time points after irradiation. Results: As expected, these small molecule therapeutics induced cell cycle arrest in the parotid salivary gland as measured by flow cytometry. Hyperphosphorylation of histone H1 has been shown to be an effective biochemical marker for cyclin-dependent kinase inhibition. Irradiation with IGF-1 was found to decrease phosphorylation of histone H1, which corresponds with G2/M arrest. Current studies are focusing on histone H1 phosphorylation and salivary gland physiological function following treatment with cyclin-dependent kinase inhibitors and irradiation. Conclusion: These small molecule therapeutics may be valuable for protecting salivary glands during the treatment of head and neck cancer. This work has been supported by: R01 DE18888.