Quantitative histological changes in a human melanoma xenograft following exposure to single dose irradiation and hyperthermia.

The purpose of the present paper is, in terms of quantitative histology, to explain the growth response of a human melanoma xenograft after exposure to single dose irradiation (7.5 Gy, 15.0 Gy, and 25.0 Gy) and hyperthermia (42.5 degrees C for 60 min). Data from several experiments on the mitotic activity, the occurrence of different modes of cell death and reproductively dead cells in the tumors are discussed. The tumor cell proliferation is only transiently reduced after 7.5 Gy and 15.0 Gy, and tumor regression mainly results from an increased cell loss. Cell loss through apoptosis and cell disintegration during mitosis show a dose-dependent increase after irradiation. Although the fraction of necrosis, relative to the number of tumor cells, increases after 7.5 Gy and 15.0 Gy, the cell loss through necrosis, that is, the production of necrosis, is probably reduced. Compared to the cell loss through apoptosis and mitotic death, the removal of necrosis is probably less important in determining the regression rate of the tumors after 7.5 Gy and 15.0 Gy. After 25.0 Gy the cell production is markedly reduced, and cell loss increases, partly due to radiation injury to the vascular system, resulting in necrotization of the tumor core. Thereafter, the tumor regression rate depends mainly on the rate of necrosis removal. The mitotic activity of remaining cells is not reduced after hyperthermic treatment, and the tumor growth response is a result of an increased cell loss. Although the occurrence of apoptosis and cell disintegration in mitosis increases after hyperthermia, these modes of cell loss are of minor importance for the tumor regression after treatment. The increased cell loss is mainly due to massive necrosis formation in the central tumor areas, a result of heat injury to tumor blood vessels. After necrotization of the tumor core, the regression rate depends mainly on the rate of necrosis removal.