Porfiromycin as an adjunct to radiotherapy in young and old mice

Radiobiological data and measurements with O2 microelectrodes show that EMT6 tumors implanted into aged mice have a higher proportion of radioresistant, hypoxic cells than do tumors implanted into young adult animals; radiation is less effective in killing cells in tumors in old mice than in tumors in young adult mice. The studies reported here examine the effects of porfiromycin (POR), a bioreductive alkylating agent shown previously to be preferentially toxic to hypoxic EMT6 cells in vitro and in solid tumors in young adult mice. POR was effective in attacking the hypoxic cells of tumors in aged mice; regimens combining POR with x-rays overcame the radioresistance of tumors in the old animals. Comparisons of the distribution of 3H-labeled POR in young and old mice showed that tumors in aged mice had a slightly larger proportion of areas with necrotic features, which bound higher levels of tritiated POR than did healthy tumor regions without necrotic features. Studies of histology, lissamine green distributions, binding of tritiated POR, and radiation and POR cytotoxicity suggested that tumors in old mice contained a larger proportion of poorly perfused tumor cells, and that cells in these regions were resistant to radiation and sensitive to POR. Studies of the distribution of POR in normal tissues and of the toxicity of POR to bone marrow progenitor cells (CFU-GM) revealed no differences between young and old animals, showing that the differences observed in tumors reflected differences in the microenvironments within the tumors, rather than differences in the processing of drug in young and old animals.