Therapeutic advantage of hypoxic cells in tumors: a theoretical study The presence of hypoxic cells in solid tumors has long been considered a problem in cancer treatment, particularly for radiation therapy but also for treatment with some anticancer drugs. Three general strategies are being actively explored to overcome the problem: oxygenating the tumor, sensitizing the hypoxic cells to radiation (or chemotherapy), or killing the hypoxic cells (with a hypoxic cell cytotoxin). In the present study, we have examined the impact of each of these three strategies on a standard radiation therapy regimen (30 doses of 2 Gy), using either of two major assumptions: full reoxygenation or no reoxygenation of the tumor cells. We demonstrate that a hypoxic cell cytotoxin can produce a level of tumor cell killing higher (by several orders of magnitude) than that produced by full oxygenation of a tumor or by use of an optimum hypoxic cell radiosensitizer, provided the cytotoxin kills more than approximately 50% of the hypoxic cells each time it is given. The only assumption that makes a difference is whether reoxygenation occurs: In the worst case (ie, no reoxygenation), the hypoxic cell cytotoxin performs only as well as an optimum radiosensitizer. The analysis shows that hypoxic cells in tumors can be a major therapeutic advantage. Therefore, we recommend that research efforts be concentrated on development of superior hypoxic cell cytotoxins rather than improved hypoxic cell radiosensitizers and that, in parallel, emphasis be placed on development of agents to increase hypoxia. 