ABSTRACT
In this chapter the physical concepts of “target theory” are reviewed in light of the different mechanisms of cell killing described by the linear-quadratic (LQ) equation. An improved understanding of the ionizing events in tumor cells is provided by microdosimetry and nanodosimetry. The majority of radiation dose deposited in the nuclei of tumor clonogens occurs as discrete events of low energy (60 eV on average) in mainly cellular water (70%–75% of a cell’s mass), each of which will produce only a few free radicals that can diffuse 2-3-nm to DNA and produce potentially lethal lesions. These events are likely responsible for the simple molecular lesions associated with βo-inactivation. A much smaller proportion of the delivered dose involves larger amounts of energy (~700 eV) deposited in much larger volumes of 10-30-nm dimensions where electrons are stopped. These can produce multiple and local DNA lesions. Electron track-ends, Auger cascades and charged-particle radiations deposit much of their energy in this manner, which can inflict several chemical changes in close proximity in the DNA target (intra-and interchromosomal) that are heterogeneous and irreparable. These radiation events probably account for α-inactivation. The DNA in mitotic cells and in condensed chromatin of interphase nuclei is most susceptible to these larger energy deposition events. As regards molecular targets, an improved understanding of cellular DNA in its various conformations throughout the cell cycle and in different cell compartments will be important for describing α-and βo-inactivation mechanisms. Both mechanisms involve the indirect effects of water radicals in which OH˙ and molecular oxygen play decisive roles.
