7- Tissue Radiation Biology
L. Cellular "Radiosensitivity". 1.1. Differentiation. 2. Cell Populations. 3. Radiation Response of Cells. 3.1. Vegetative lntermitotic Cells (VIM).
Differentiating lntermitotic Cells (DIM). 3.3. Multipotential Connective Tissue Cells. 3.4. Reverting Postmitotic Cells (RPM). 3.5. Fixed Postmitotic Cells (FPM). 4. Tissue Response to Radiation. 4.1. Tissue Organization. 4.2. Mechanisms of Damage in Normal Tissues. 5. Measurement of Radiation Damage in Tissues. 5.1. Assays of Tissue Response. 5.2. Clonogenic Assays. 5.3. In Situ Assays. 5.4. Transplantation Assays. 5.5. Functional Assays. 5.6. Lethality. 6. Shapes of Survival Curves for Acutely Responding and Late Responding Normal Tissues.
Tissues and organs are made up of cells — in some cases just a few cell types, in other cases many cell types. The underlying assumption throughout this chapter is that the visible and detectable changes induced by radiation, whether at the tissue level or the whole-body level, are due to the killing and subsequent depletion of critical "target" cells in that tissue. In some tissues and organs this target cell has been identified and can be quantified; in others it remains elusive and often controversial despite the efforts of many investigators to identify it. Nonetheless, it is assumed that it is the depletion of these target cells that results in the types of damage to be discussed in this chapter.
Keeping this basic premise in mind, the response of an organ or tissue to radiation depends on two factors:
The inherent sensitivity of the various cell populations in that tissue or organ.
The turnover kinetics of each population in the tissue (Do they divide, and if so, how often?).
Inherent sensitivity as defined by the loss of reproductive capacity for all ceils is similar both in vivo and in vitro (see Chapter 6), yet normal tissues differ widely in their responses to radiation. Thus it must be the "when" and "if individual cells divide that account for the apparent differences in tissue radiation response. Before tissue response to radiation can be discussed it is necessary to understand the term "sensitivity" and the factors that govern both the sensitivity of individual cells to radiation and the expression of damage following irradiation.
Cellular “Radiosensitivity”
The role of cell division in the radiation response of tissues and organs was appreciated as early as 1906 by two scientists, Bergonie and Tribondeau. Based on physicians' reports that (I) x-rays appeared to destroy the cells of a malignant neoplasm (tumor) without permanently harming the adjacent healthy tissue, and (2) some tissues were damaged by doses of radiation that did not appear to harm other tissues, Bergonie and Tribondeau deduced that cell division was critical to this "selective" cell killing. They performed experiments on rodent testicles to further define this observed selective effect of radiation. They chose the testes because they contain mature cells (spermatozoa), which perform the primary function of the organ, and also contain immature cells (spermatogonia and spermatocytes), which have no function other than to develop into mature, functional cells. Not only do these different populations of cells in the testes vary in function, but their mitotic activity also varies — the immature spermatogonia divide often, whereas the mature spermatogonia never divide.
After irradiation of the testes, Bergonie and Tribondeau observed that the immature dividing cells were damaged after lower doses than were the mature nondividing cells. Based on these observations of the response of the different cell populations in the testes, they formulated a hypothesis concerning radiation sensitivity for all cells in the body. In general terms, their hypothesis states that ionizing radiation is more effective against cells that are actively dividing, are undifferentiated, and have a long dividing future.
Bergonie and Tribondeau defined cell sensitivity in terms of specific cellular characteristics of the cells studied, mitotic activity and differentiation rather than on the radiation. Bergonie and Tribondeau's criteria for cellular radiation sensitivity can be interpreted as determinants of the inherent susceptibility of a cell to radiation damage.
In 1925 Aneel and Vitemberger modified the hypothesis of Bergonie and Tribondeau by proposing that the inherent susceptibility of any cell ю damage by ionizing radiation is the same, but that the time of appearance of radiation-induced damage differs among different types of cells. In a series of extensive experiments in mammalian systems, they concluded that the appearance of radiation damage is influenced by two factors: (1) the biologic stress on the cell, and (2) the conditions to which the cell is exposed pre-irradiation and postirradation. On this latter point, Ancei and Vitemberger were well ahead of their time in their thinking, for now, more
than 50 years later, it is well known that postirradation conditions can and do affect cellular sensitivity by allowing the expression (or repair) of potentially lethal damage (see Chapter 6).
Ancel and Vitemberger postulated that the greatest influence on radiosensitivity is the biologic stress placed on the cell, and that the most important biologic stress on the cell is the necessity for division. In their terms, all cells will be damaged to the same degree by a given dose of radiation (i.e., all cells are similar in their inherent susceptibility), as has been shown, but the damage will be expressed only if and when the cell divides. Ancel and Vitemberger were truly clever in their thinking, for they recognized that if all cells had a common target for radiation, then a given dose would deposit the same amount of energy and produce the same amount of damage irrespective of the mitotic status of the cell. However, cells which divided quickly would simply express the damage sooner and appear "sensitive" compared with those that divided more slowly, and would express their damage later and thus appear "resistant."
Thus, in the early twentieth century it was suggested that it was not only cell division and cell turnover that were important in the expression of radiation injury, but also the kinetics of turnover, i.e., whether it occurred rapidly or slowly.
process by which immature spermatogonia become mature spermatozoa is termed differentiation (Fig 7-1).
Another example of a differentiated cell is the erythrocyte (red blood cell, or RBC). .lust as the spermatozoan is the mature end cell in the testis, the RBC is the mature, differentiated cell in the red cell line of the hemopoietic system. The major function of the RBC is to transport oxygen to cells of the body. Not only is this cell specialized in function, but it also is specialized in structure; the RBC differs from other cells in the body in that it does not have a nucleus. Therefore, both morphologically and functionally, RBCs are differentiated cells. The average lifetime of RBCs in the circulating blood is 120 days, necessitating a continual replacement of these cells by newly produced cells. The stem cell (see below) for the RBC, the erythroblast, is present in the bone marrow and is an undifferentiated cell that divides and supplies cells which will differentiate to become erythrocytes.