REDOX GENERATION OF NITRIC-OXIDE TO RADIOSENSITIZE HYPOXIC CELLS

Purpose: Previous studies have shown that nitric oxide (NO) delivered from NO donor agents sensitizes hypoxic cells to ionizing radiation. I n the present study, nitroxyl (NO-), a potential precursor to endogeno us NO production, was evaluated for hypoxic cell radiosensitization, e ither alone or in combination with electron acceptor agents. Methods a nd Materials: Radiation survival curves of Chinese hamster V79 lung fi broblasts under aerobic and hypoxic conditions were assessed by clonog enic assay. Hypoxia induction was achieved by metabolism-mediated oxyg en depletion in dense cell suspensions, Cells were treated with NO- pr oduced from the nitroxyl donor Angeli's salt (AS, Na2N2O3, sodium trio xodinitrate), in the absence or presence of electron acceptor agents, ferricyanide, or tempol, NO concentrations resulting from the combinat ion of AS and ferricyanide or tempol were measured under hypoxic condi tions using an NO-sensitive electrode. Results: Treatment of V79 cells under hypoxic conditions with AS alone did not result in radiosensiti zation; however, the combination of AS with ferricyanide or tempol res ulted in significant hypoxic radiosensitization with SERs of 2.5 and 2 .1, respectively. Neither AS alone nor AS incombination with ferricyan ide or tempol influenced aerobic radiosensitivity, The presence of NO generated under hypoxic conditions from the combination of AS with fer ricyanide or tempol was confirmed using an NO-sensitive electrode. Con clusion: Combining NO- generated from AS with electron accepters resul ts in NO generation and substantial hypoxic cell radiosensitization. N O- derived from donor agents or endogenously produced in tumors, combi ned with electron accepters, may provide an important strategy for rad iosensitizing hypoxic cells and warrants in vivo evaluation. (C) 1998 Elsevier Science Inc.