X-Radiation Damage to the Hypoxic Core and to the Periphery of a Tumor

The last several years have seen a gradual acceptance of the concept that tumors with necrotic centers contain cells in two quite different environments which control, to a large extent, the response of the tumor cells to radiation. The periphery of the tumor is conceived of as well oxygenated while the core, lacking an equal vascularization, is hypoxic (1, 2). It follows, according to sound radiobio-logic principles, that the oxygenated cells will incur more damage after a given dose of gamma or x irradiation than the hypoxic cells. Therefore, cells on the periphery of a large tumor are more radiosensitive than those in the center. It has been demonstrated that the peripheral cells of certain tumors exhibit damage in excess of that expressed by the cells in the hypoxic centers (2–4). This result is the rationale for treating the central tumor areas to a higher dose than the peripheral ones (1, 5). The concept is a reasonable one, but it may be too simple a view of what is in reality a complexity of interacting factors. If we are to assume that large tumors are regularly composed of an anoxic center and a well vascularized outer boundary and that the hypoxic cells incur less damage than the oxygenated ones, can we then conclude that the cells in the center will consistently be the most resistant to the lethal effects of radiation? The presence of necrotic center is certainly evidence of an unsupportive environment. In many instances the lack of support must be nutritional only, since many tumor cells are not dependent on oxygen to produce energy. Cells which are still viable in the hypoxic environment could then incur less damage due to reduced oxygen tension and retain the capability of repairing the damage done equally as well as oxygenated cells. In contrast to this situation, it seems possible that certain tumors are populated with cells unable to produce ATP in the absence of oxygen. These cells then would have the initial advantage of less induced damage in an hypoxic environment, but the subsequent disadvantage of being unable to repair any of the damage as a consequence of their oxygen deprivation (7). This latter disability could leave them at a competitive disadvantage with oxygenated cells. When this situation arises the central core of cells could be more sensitive to the effects of radiation. The present report is a result of a pilot investigation to determine in vivo the comparative sensitivities of the vascularized peripheral cells and the cells from the necrotic center in a particular tumor. The assay system was based on the assumption that when a large mouse tumor (greater than 2 cm) was irradiated and cells from the hypoxic region and the periphery were injected into untreated mice, the difference in sensitivities of the two regions would show as differences in the success of transplant.