Role of Antioxidant Enzymes in the Induction of Increased Experimental Metastasis by Hydroxyurea

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Abstract
Background : Treatment of tumor cells with hydroxyurea and other DNA-damaging agents has been shown to increase the experimental metastatic potential of these cells. Purpose : We sought to elucidate some of the biochemical and genetic changes that promote tumor cell metastasis in hydroxyurea-treated cells. We hypothesized that drug treatment induces resistance to oxidative damage and that elimination of this resistance reverses the drug-induced experimental metastatic capabilities of tumor cells. Methods : We examined the effect of hydroxyurea treatment on B16 melanoma cells with respect to experimental metastatic potential, resistance to hydrogen peroxide (H 2 O 2 ), glutathione peroxidase activity and messenger RNA (mRNA) level, glutathione reductase activity, glutathione levels, glutathione-S-transferase activity, and catalase activity and mRNA level. Results : Hydroxyurea-treated cells were transiently more metastatic following intravenous injection in syngeneic mice and transiently more resistant than untreated cells to exogenous H 2 O 2 . Hydroxyurea-induced experimental me-tastases and H 2 O 2 resistance were eliminated by depletion of intracellular glutathione with buthionine sulfox-imine. Glutathione peroxidase activity and mRNA level, glutathione reductase activity, and reduced glutathione levels were all transiently increased in hydroxyurea-treated cells, whereas the increase in glutathione-S-transferase activity was sustained. Catalase activity was modestly increased with no increase in its mRNA levels. Conclusions : In B16 melanoma cells, experimental metastasis induced by hydroxyurea appears to depend on a process that requires glutathione. Hydroxyurea treatment also induces resistance to exogenous H 2 O 2 , which may be due to induction of glutathione and antioxidant enzyme activity. Implications: The role of antioxidants in B16 melanoma cells offers new insights into the metastatic process and the cellular response to chemotherapy. [J Natl Cancer Inst 85: 711–721, 1993]

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