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Antioxidant system (AOS) regulates physiological levels of reactive oxygen species (ROS). In regulatory pathways of the cell ROS can function as signaling molecules, in immune response they are used for destruction of infectious agents. ROS are produced constantly in biochemical reactions, but their overproduction or depletion of AOS capacities leads to oxidative stress and damages of membranes, proteins and nucleic acids. AOS functions in tumors are disturbed because of metabolic reprogramming and different components of AOS in cancer cells can be involved in processes that are absent in normal cells. One of that processes is exemplified by the involvement of the system regulating the reduced glutathione (GSH) levels into mechanisms of drug resistance. Development of resistance to alkylating drugs is accompanied by substantial increase in GSH levels while the activity of the superoxide dismutase and catalase was not changed independent on resistance inducer used. Therapy of tumors resistant to alkylating agents with non-alkylating therapeutic agents causes decrease in GSH and activity of AOS enzymes. Found effects depend on both compound used for resistance induction and therapeutic agent which demonstrates complexity and versatility of AOS regulation mechanisms. Being a source of signaling ROS, AOS is closely related to other regulatory systems. The central genome stability factor, tumor suppressor p53, proved to be a connection knot between processes of cell division/death and AOS. Impact of DNA damaging factors on the cell is accompanied by both activation of p53-dependent pathways and modulation of expression of genes encoding AOS enzymes. Several hypotheses explaining these phenomena as a direct action of p53 on AOS genes have not been confirmed. Our data demonstrate an indirect influence of p53 on these genes which suggests that separate protective systems are coordinated via signaling network of cell cycle regulators and transcription factors. Experimental data are presented that demonstrate the modulation of AOS during drug resistance development and therapy of resistant tumors, response of AOS genes on chemotherapy agents, and the relation of the response to functions of p53.