Acute hypoxia in tumors: implications for modifiers of radiation effects

Radioresistant hypoxic cells have been shown to occur in nearly all the animal tumors studied to date. Furthermore, there is a large amount of evidence, albeit indirect, that hypoxic cells exist and impair the effectiveness of radiation therapy in some human cancers. Surprisingly little is known, however, about the natural history of such hypoxic cells. Recently in our laboratories, we have developed methods which enable us to select and analyse cells from tumors as a function of their distance from the tumor blood supply. Utilizing this technique, we have been able to demonstrate using SCCVII tumors greater than or equal to 500 mg that even cells close to the blood supply may become hypoxic at any particular time. This information provides direct evidence that, at least for that tumor, hypoxia can result from transient fluctuations in blood perfusion. The existence of acutely, as well as, chronically hypoxic cells within tumors has several implications for treatment strategies. Treatments designed to increase oxygen content in the blood may not be particularly effective in sensitizing acutely hypoxic cells. However small, freely diffusable radiosensitizers would distribute throughout the tumor, and should be equally effective in sensitizing both acutely and chronically hypoxic cells to radiation. Acute hypoxia may thus be the best possible indicator for the use of chemical radiosensitizers in radiation therapy.