60 80 Total Dose (Gy)

figure 3.1. The concept of therapeutic ratio for radiation therapy under conditions in which the relationship between the normal tissue tolerance and tumor control dose-response curves is optimal (upper panel), unacceptable (middle panel), and acceptable (lower panel).

or indirect effects produced by intermediate radiation products resulting from interactions with water, which constitutes up to 90% of a cell or tissue as calculated on a weight basis. The most highly reactive species produced by the radi-olysis of water is the hydroxyl radical (•OH), although there are many other types of free radicals produced by ionizing radiation, including DNA free radicals resulting from direct ionizations. These free radicals are generated within 10-2 to 10-12 seconds and subsequently cause chemical damage to DNA. It has been determined that ionizing radiation-induced cell killing in mammalian cells (including human tumor cells) results from a greater contribution (@70%) of initial indirect ionizing effects on water than direct effects on essential biomolecules, principally DNA. These ionizing radiation-produced free radicals are highly reactive chemically within the cell and undergo a cascade of reactions to either acquire new electrons or to rid themselves of unpaired electrons, typically resulting in breakage of chemical bonds in DNA in very localized areas, called clusters, or multiply damaged sites. Because DNA is considered to be the most essential cellular biomolecule, the types of DNA damage caused by this sequence of initial energy deposition, production of free radicals and subsequent clustered breakage of chemical bonds can include DNA single-strand breaks (SSB), DNA doublestrand breaks (DSB), DNA crosslinks, and DNA base damage. The creation of a DSB and, more specifically, an unrepaired DSB is considered the most cytotoxic DNA lesion resulting from ionizing radiation damage.4,5 The molecular and biochemical processes involved in ionizing radiation damage and repair in human normal and malignant tissues are reviewed in the next section.

At the cellular level, the biologic effects of these initial physical interactions of ionizing radiation with biologic materials and the secondary chemical effects (i.e., DNA effects) can result in a cell's loss of reproductive capability. Functionally, the consequence of this reproductive loss can result in terminal differentiation, accelerated senescence, necrosis, or apoptosis.6,7 A cell that has been lethally damaged by ionizing radiation may undergo a few cell divisions before death, and this lethally damaged cell's progeny are also destined to die. In the radiation biology laboratory, the radiation sensitivity of a cell (both normal and malignant) can be quantitated by analysis of cell survival curves. A radiation survival curve plots the fraction of cells surviving on a log scale against the radiation dose given (in cGy or Gy) on a linear scale (Figure 3.2). Survival is determined by the ability of a cell to form a macroscopic colony, usually defined as more than 50 cells (@5-6 cell divisions). A typical radiation survival curve for a mammalian cell population has an initial "shoulder" in the low-dose region (up to 1-3Gy), followed by a terminal exponential slope. The importance of this exponential relation is that, for a given radiation dose increment, a constant proportion (not a constant number) of cells are killed by ionizing radiation.6,7 The shoulder region indicates a reduced efficiency of cell killing or, conversely, a higher efficiency of repair of sublethal or potentially lethal ionizing radiation damage. The resulting survival curve for mammalian cells based on a standard clonogenic survival assay is best described by a linear quadratic (LQ) model, according to the following formula:

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