An antinitrosative system as a factor in malignant tumor resistance to the cytotoxic effect of nitrogen monoxide

Inhibition of growth of a transplanted solid tumor in BDF1 mice bearing Lewis lung carcinoma cells on days 1–5 and 7–11 after tumor transplantation was observed at daily intraperitoneal administration of an aqueous solution of binuclear form of dinitrosyl iron complexes with glutathione at a dose of 200 μmol/kg (relative to one Fe(NO)2 group in the complexes). Inhibition of tumor growth during the administration of complexes (for 11 days) was 70 and 85% when an iron complex: free glutathione ratio in solution was equal to 1: 1 and 1: 10, respectively. Accelerated tumor growth that was faster than in the control began after cessation of dinitrosyl iron complex administration. The selective accumulation of dinitrosyl iron complexes in the tumor, as well as the accumulation of nitrosyl complexes of heme proteins was detected by the EPR method. The latter were observed in the tumor and control animals. It is hypothesized that delayed tumor development during administration of the binuclear form of dinitrosyl iron complexes to mice is caused by inactivation of heme-containing proteins under the action of NO released from these complexes, which provides antinitrosative defenses produced in malignant tumors.