Chapter 4 - Anticancer Drugs Acting via Radical Species: Radiotherapy and Photodynamic Therapy of Cancer

Abstract

Chapter 4 deals with the origin and roles of reactive oxygen species (ROS) and local oxidative stress associated to the imbalance between ROS production and the action of antioxidant defence systems. Membrane phospholipid peroxidation initiated by the attack of a hydroxyl radicals is explained, as well as the generation of malondialdehyde and its consequences. The mechanisms of DNA strand scission, oxidation of DNA bases and nuclear proteins, as well as the defense mechanisms that counteract this damage, are discussed in detail. Anthracyclines are studied as promoters of ROS with the consequent induction of apoptosis, although they are also included in Section 6 of Chapter 7 because of their activity as topoisomerase II poisons. We also discuss their association with chelating agents such as dexrazoxane to prevent the induced cardiotoxicity and how the anthracycline-induced ROS may generate formaldehyde and anthracycline/formaldehyde adducts. The mechanisms that explain how chartreusin (NSC 5159), elsamicin A, the bleomycins (BLMs) and the enediyne antibiotics generate radical species that cause single strand scission of DNA are explained. Radiotherapy is based on the generation of hydroxyl radicals from the homolytic fragmentation of water molecules upon local application of ionizing radiation, and is less efficient in hypoxic cells because in the absence of oxygen biomolecule radicals are repaired by glutathione. We study several hypoxic radiosensitizers that increase the efficiency of radiotherapy, and we also discuss how the normal tissues surrounding the tumor may be protected against the radiation damage with radioprotective compounds. Finally, we study the photodynamic therapy (PDT) of cancer by using photosensitizers (PS) able to absorb harmless visible light energy and transfer it to other molecules in their vicinity.