Tumor cells at very low
oxygen tensions are known to be about three times more resistant to killing by ionizing radiation. Since cells at intermediate
oxygen tensions (defined here as greater than 0.1% and less than 2% O(2)) show partial radioresistance, they should be a consideration in
tumor treatment. In an effort to estimate the extent and range of oxygenation in SiHa human cervical
carcinoma xenografts, patterns of cell killing and DNA damage by radiation and two bioreductive drugs, PD-144872 and
RSU-1069, were compared to those seen in SiHa cells grown as spheroids. These drugs produce
DNA interstrand crosslinks that are largely responsible for cell killing, and the degree of crosslinking increases as the oxygenation is reduced. About 60% of the cells in SiHa xenografts exhibited
drug-induced crosslinks, but only about 35% showed extensive crosslinking indicative of
hypoxia below 0.1%
oxygen. Patterns of toxicity and DNA damage in xenografts were comparable to those of spheroids equilibrated with about 2%
oxygen, indicating that most cells in the xenografts exhibit some radioresistance due to lack of
oxygen. Similarly,
pimonidazole binding indicated that about 60% of the cells in SiHa xenografts were either intermediate in oxygenation or hypoxic, but only about half of those were consistent with extreme
oxygen depletion. The apparent size of the population of "intermediately hypoxic" cells has implications for the use of ionizing radiation, hypoxic cell
cytotoxins, and other
antitumor agents whose cytotoxicity is dependent on cellular
oxygen content.