Past, present, and future of oxygen in cancer research.

The first pathologists, oncologists, and medical physicists were aware that tumors were populated by an aberrant vasculature. The classic observations of Thomlinson and Gray in the 1950's established that O2 diffusion distances caused tumor to grow in cords. Tumor necrosis was observed surrounding a Krogh cylinder of viable tumor. That work helped explain earlier work by Warburg, who demonstrated a predisposition for tumors to favor anaerobic respiration, and it became the basis for 5 decades of subsequent research aimed at improving tumor oxygenation at the time of radiation. The role of O2 in modifying radiation response was attributed exclusively to the reactive free radicals that can be formed when O2 is present. These radicals produce approximately three-fold more irreparable double strand breaks in DNA. Subsequently it became clear that tumor had nutritional insufficiencies in addition to hypoxia. Ischemic regions are hypoglycemic, acidotic, have poor penetration of drugs, increased interstitial pressure, and altered immunological states. Ischemic regions can have intermittent reflow and associated redox stress. The relative impact of O2 compared to these associated phenomenon, and the degree to which hypoxia causes or follows these associated physiologic stresses, have been studied in detail. ISOTT scientists are responsible for much of the elucidation of the specific effects of O2, ADP/ATP ratios, hypoglycemia, and acidosis on tumor responses to radiation and hyperthermia. Many questions still remain.