Marija Djordjević, Jovan Ilić, Nikola M. Stojanovic

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Cisplatin is the first heavy metal compound that has been found to possess antineoplastic activity. It is effective in treating testicular, ovarian, head and neck, bladder, cervical, esophageal tumors, and small cell lung carcinoma. Approximately 1% of cisplatin that enters the cell interacts with DNA, forming DNA-cisplatin bonds. Both apoptosis and necrosis can be found in the same population of cells exposed to cisplatin, and the mode of cell death depends on the cisplatin concentration and metabolic state of the target cell. In the bloodstream, the platinum component of cisplatin binds to the blood's proteins (hemoglobin, albumin and transferrin), and other significant portion binds to the glutathione and other cysteine-rich biomolecules. Cisplatin impairs the mitochondrial and cell antioxidant defense system (decreases GSH, NADPH levels, GCH/GSSG ratio, and increases GSSG levels) leading to oxidative stress. There are three main mechanisms of cell resistance to cisplatin: (1) enhanced repair of cisplatin-induced DNA lesions, (2) decrease in uptake and/or increase in efflux and (3) inactivation of cisplatin intracellularly. The usage of cisplatin is limited due to its toxicity and side effects, which include neurotoxicity (numbness and tingling, paresthesia, reduced deep tendon reflexes), nephrotoxicity (renal insufficiency, hypomagnesemia), ototoxicity (tinnitus and bilateral high-frequency hearing loss), cardiotoxicity (changes in electric heart activity, congestive heart failure), gastrotoxicity (nausea, vomiting, and dyspepsia), etc.  So far, there  has been no effective, clinically administered, therapy for cisplatin-induced toxicity.


cisplatin, oxidative stress, drug resistance, apoptosis, toxicity

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