Induction of nitric oxide production in infiltrating leukocytes following in vivo irradiation of tumor-bearing mice

Nitric oxide (NO) has been implicated both in regression and progression of tumors due to its production by both tumor cells and infiltrating leukocytes. Ionizing radiation causes the regression of tumors, and can augment the production of NO by macrophages in vitro. We examined the cellular and systemic production of NO in mice in which radiation-resistant RIF-1 fibrosarcoma cells were implanted subcutaneously and were then either irradiated or sham-treated at the tumor site. Ten days following implantation of the tumors, CD45- tumor cells and CD45+ leukocytes were derived from resected tumors immediately after irradiation with 60 Gy, a dose previously reported to reduce tumor growth. Leukocytes from tumors of irradiated hosts produced spontaneously up to four-fold more NO than did either leukocytes from unirradiated mice or CD45- tumor cells from either unirradiated or irradiated mice. Between days 10-14 following tumor implantation, serum NO₂- /NO₃- increased in both irradiated and unirradiated mice to an equal extent, culminating in levels higher than those of non-tumor-bearing mice. Though NO production is elevated in macrophages treated with 1-10 Gy of radiation in vitro, higher doses may be required by tumor-infiltrating macrophages in vivo and thus may indicate that tumor-infiltrating macrophages are deactivated.