Radioresistance in Murine Solid Tumors Induced by Interleukin-1

Interleukin-1 (IL-1) has radioprotective activity in hematopoietic lineages and in other normal cell renewal systems, but little is known about the effects of IL-1α on the radiosensitivity of tumor cell populations. The present studies were conducted to investigate the effects of IL-1α on the radiosensitivity of clonogenic cells in RIF-1 and SCC-7 tumors. Radioresistance was detected within 2-4 h after administration of IL-1α (0.5 μg/mouse, ip) and characterized by increases in D₀,$D_{{\rm q}}$, α/β and SF2. This radioresistance was similar to that seen in tumors rendered totally hypoxic before X irradiation. Tirapazamine, a hypoxic cell cytotoxin, and IL-1α had synergistic schedule-dependent antitumor activity in vivo, suggesting that IL-1-induced radioresistance in vivo is due to hypoxia. Radioresistance induced by IL-1α was transient, and the data suggested reoxygenation within 12 h. In vitro, IL-1α had no direct effect on the radiosensitivity of SCC-7 cells in tissue culture under aerobic conditions. However, an increase in D₀, α/β and SF2 was seen in clonogenic tumor cells from primary cultures treated with IL-1α under aerobic conditions. Superoxide dismutase and catalase prevented the induction of radioresistance by IL-1α in vitro, suggesting that oxidative responses from tumor macrophages after administration of IL-1α may be responsible for induced radioresistance by IL-1 in vitro. Although oxidant stress induced by IL-1 may play an important role in the activity of IL-1α both in vivo and in vitro in our models, the mechanisms by which such responses modulate tumor radiosensitivity in vivo and in vitro are likely quite different.