Radio- and Chemosensitivity

The most important effect of radio and chemotherapy is the activation of p53, a central regulator of cell growth and cell death. Both treatments induce cell damage as well as damage to the DNA and thereby activating this important protein. Once transformed into its activated form, p53 can initiate cell cycle arrest in order to prevent cells from dividing before their damaged DNA has been repaired. If the cells are not able to repair the DNA damage, p53 activates a cellular program resulting in cell death.

The treatment of tumors with p53 mutation remains challenging, because these degenerated cells are not able to enter apoptosis and continue with proliferation. Thus, the tumor is progressive or even metastasize. This is the reason, why patients with p53 mutations have a poor response to radio- or chemotherapy. Therefore, p53 plays a central role in the occurrence of resistance and simultaneously acts as an important factor to overcome resistance.

Many solid tumors, including head and neck carcinomas, have a functional loss of p53, caused by mutations in the DNA-binding domain of p53 leading to structural changes and thereby to a loss of its transcriptional activity. Besides the genetic variations of the TP53 gene itself, the expression of viral oncogenes such as the E6 protein of the human papillomavirus (HPV) leads to a functional inhibition of the p53 protein. Furthermore, mutations in the genes MDM2 and p14ARF are also very frequent, whereby their important control function is influenced by p53. In addition to changes affecting the p53 network, there is a variety of other molecular mechanisms influencing the effectiveness of therapy in tumor and normal tissues. Further research is required to understand the molecular mechanisms and their interaction as well as to improve therapy efficiency.