Zherdieva P. I., Gorelaya M. V., Osadcha O. V.

Oles Honchar Dnipropetrovsk National University

BIOCHEMICAL MECHANISMS OF CISPLATIN CYTOTOXICITY

Cisplatin [cis-diamminedichloro platinum (II)] or cis-DDP, is of great value in the treatment of cancer. Indeed, carboplatin and cisplatin analogue [cis-diamine-1, 1-cyclobutanedicarboxylate platinum (II)] are among the most frequently used anticancer drugs today.

The biological activity of cisplatin was discovered about 125 years after the initial report of its synthesis and characterization. Although the synthesis and characterization of cisplatin was first reported in 1845 by Peyrone, its anti-cancer properties have gone unnoticed until the mid-1960s, when Rosenberg and his colleagues studied the effect of electric fields on the growth of Escherichia coli. Platinum electrodes released redox reactions which provoked some platinum complexes to complete stop cell division in bacterial rods. The platinum complexes formed by cisplatin were identified as the primary anti-proliferative agent. In subsequent years cisplatin has become one of the most widely used drugs in cancer chemotherapy.

Cisplatin is highly effective in the treatment of testicular and ovarian cancer and also widely used for the treatment of bladder, cervix, head and neck, esophageal and small cell lung cancer. Despite the success, cisplatin has several disadvantages, which include serious side effects, such as nephrotoxicity, neurotoxicity, ototoxicity, nausea and vomiting. These toxic effects limit the dose that can be applied to patients. Cisplatin also has limited solubility in water and injected intravenously, what is a major inconvenience for the patient treatment. Although cisplatin is widely used in clinic, its applicability is still limited to a relatively narrow range of tumor types. Some tumors such as colorectal and non-small cell lung cancer have intrinsic cisplatin resistance, while others, such as ovarian or small cell lung cancer, develop acquired resistance after the initial treatment.

It has emerged from these studies that the biochemical mechanisms of cytotoxicity of cisplatin include drug binding DNA and non-target, and further the induction of cell death by apoptosis, necrosis or as a heterogeneous population of cells which forms a tumor mass.

The tumor resistance to cis-DDP in combination with cisplatin toxicity stimulated the search for other active antitumor platinum complexes with improved pharmacological properties. Only registered platinum drug that consistently has antitumor activity against cisplatin resistant tumors, such as colorectal cancer, is oxaliplatin [trans-L-1, 2-diaminocyclohexaneoxalatoplatinum (II)]. There are three currently approved platinum anticancer drugs in clinical use by the U. S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) – cisplatin, carboplatin and oxaliplatin.

Although a large number of biochemical studies performed on cis-DDP activities have not clearly defined the molecular basis of tumor resistance to this drug in any cell type, at least, they have identified several mechanisms that may contribute to this process. Resistance to cisplatin is typically considered a multifactorial phenomenon that occurs mainly because of (I) reduction in accumulation of the drug, (II) inactivate the thiol species, (III) increased repair of platinum-DNA adducts, and (IV) an increase in cis-DDP adducts fault tolerance and cell death pathways. These mechanisms are dependent on cell line stability.

An alternative way to circumvent the resistance to cisplatin and to improve its antitumor activity is use of biochemical modulation strategies. This new approach involves a combination of cisplatin with drugs that interfere with specific cisplatin-resistance pathways, while the biochemical mechanisms that modulate cisplatin-resistance to an increasing number of drugs have been discovering.