Chapter 12 - Cancer therapies inducing DNA damage

Abstract

The induction of DNA damage has been employed as an anticancer strategy for more than 100years, first starting with the use of radiation to treat stomach cancer followed by the first uses of DNA-damaging chemotherapy to treat childhood leukemia. Since those early pioneers, our understanding and application of radiotherapy, together with the discovery of many more anticancer chemotherapies, has revolutionized the clinical management of cancer. The broad mechanism of action for those earliest cancer treatments and the majority of therapies still used today are via the induction of DNA damage, resulting in cell death. However, therapy-induced DNA damage can sometimes be insufficient to induce cell death and can potentially be repaired via the DNA damage response and a variety of DNA repair pathways leading to treatment resistance. In normal and cancer cells, both the response to DNA damage and process of DNA repair are tightly regulated via gene expression and post-translational regulations such as phosphorylation. In addition, the DNA itself is in part controlled by the physical structure of chromatin, which is controlled by DNA methylation and various histone modifications. In this chapter, we discuss the various types of DNA damage-inducing therapies used in the clinical management of cancer. The types of therapies, their clinical use, and their mechanisms of action are highlighted, to provide a primer with which to understand the impacts of different treatments on both normal and cancer cells. This knowledge is essential to uncover new ways to improve cancer treatment, potentially by the addition of molecularly targeted drugs, such as epigenetic-modifying therapies, to existing upfront treatment regimens.