GENETIC TOXICITY OF CYTOKINES

Review of the literature shows that such cytokines as human interferon s alpha and gamma, tumor necrosis factor alpha, epidermal growth facto r and interleukin-2 may exhibit genotoxic properties in human peripher al blood lymphocyte cultures. For all above cytokines, except interleu kin-2, parabolic-like relationship between the dose and the frequency of sister chromatid exchanges was found, Although the mechanisms of th ese genotoxic actions remain largely unknown, generation of free radic als or interaction with enzymes such as DNA topoisomerase II may be su spected. Human interferon alpha also may be considered as an antimutag enic compound in human cells. Human tumor necrosis factor alpha has be en reported to enhance cytotoxicity and DNA fragmentation produced by DNA topoisomerase II-targeted anticancer drugs. At the same time, it h as some radio- and chemoprotective properties in vitro and in vivo, De spite these facts, the question about genotoxicity of cytokines is not answered. Some problems must be resolved before receiving the final a nswer. First, much more cytokines must be tested for their genotoxic a ctivity. Second, appropriate test-systems must be designed. Third, gen otoxicity studies of cytokines must account for cytokine interaction i n the cytokine network as well as for such cytokine-induced effects as cytotoxicity and apoptosis. Fourth, in each case, it is necessary to have experimental evidence that observed genotoxic effects were caused by cytokine under investigation and not by the other factors.