Genetic Polymorphisms and Cisplatin- Related Nephrotoxicity

Cisplatin is one of the most widely applied antineoplastic agents used to treat different types of solid tumours. However, its use is limited by serious sideeffects including nephrotoxicity. Cisplatin accumulates in proximal tubule and forms nephrotoxins that causes proximal cell injury and thereby leads to nephrotoxicity. Cisplatin enters these proximal cells by organic transporter molecules (OCT). Genetic polymorphism of these molecules and other membrane transport proteins that regulate cisplatin accumulation may influence cisplatinrelated nephrotoxic outcome. Variations of DNA repair enzymes, e.g., ERCC1, eIF3, MMS 19L, and metabolic enzymes involved in platinum detoxification, e.g., GSTT1, GSTM1 may also have important role in the generation of nephrotoxicity. Polymorphisms of these genes can be used as predictive tools for such adverseevents in an individual. Thus chemotherapy can be modulated accordingly without compromising with antineoplastic activities of cisplatin. Conversion of cisplatin to nephrotoxin starts with the formation of platinumglutathione conjugates (PtGSH) with the activity of GSHtransferase. This conjugate is then transported out of the cell [7] probably by the action of efflux pump protein [1]. It is then metabolized on cell surface through γglutamyl transpeptidase (GGT) expressed on the surface of the proximal tubular cells to form platinumcysteinylglycine conjugate, then to platinumcysteine conjugate by another cell surface protein aminopeptidase N. Platinumcysteine conjugate then enters the cell and converted to highly reactive thiol with the activity of cysteine S-conjugate β-lyase, an intracellular enzyme [3,7]. Reactive thiol then interacts with the essential intracellular proteins which cause toxicity [7]. Nephrotoxins cause proximal cell injury, which leads to nephrotoxicity involving multiple pathways. While higher doses of cisplatin induce necrosis, a lower concentration induces apoptotic death of these cells [9]. Both nuclear and mitochondrial DNA damage, oxidative stress (caused due to increased freeradical production and decreased antioxidant production), inhibition of protein synthesis, mitochondrial dysfunction, a series of inflammatory changes, fibrogenesis etc. are the probable mechanism of renal cell injury [3,10]. Considerable interindividual differences exist in platinum drugrelated toxicity. While some individuals undergoing treatment may show toxic effect for a particular regimen, others may not, and also the grade of toxicity can vary from mild to severe. In general several factors may be responsible for differential treatment outcome for the same medication. They can be categorized as physiological factors like age, sex, disease state, circadian rhythm, health status, or environmental factors like exposure to carcinogens, tobacco smoke, alcohol, co-medication or dietary constituents etc., and genetic factors [11]. Ethnicity may also account for drug-response variability [12]. While effects of nongenetic factors on drug response may be transient, effects of genetic factors may be stable as they generally lead to permanent changes in proteins those are involved in drug Introduction Cisdiamminedichloroplatinum (cisplatin) is one of the most commonly used present day chemotherapeutic agents. It is used to treat a wide range of cancers including head and neck, lung, gastrointestinal tract, ovarian and genitourinary cancers. However, doselimiting toxicity is often associated with cisplatin. It is known that cisplatin works more effectively with dose escalation, but significant risk for nephrotoxicity is often associated with higher doses [1]. Recovery of renal function occurs over a period of 2-4 weeks, although lack of recovery can also take place [2]. Kidney accumulates cisplatin in much higher concentration in comparison to other organs and is the major route of its excretion [3]. Five times higher cisplatin concentration was observed in proximal tubular epithelial cells in comparison to serum [4]. Highest accumulation of cisplatin occurs in S3 segment of proximal tubule followed by the distal collecting tubule and the S1 segment of proximal tubule [5]. Cisplatin nephrotoxicity may be presented in various ways of which the most serious presentation is acute kidney injury, which occurs in 20-30% of patients despite hyperhydration and forced Diuresis [6]. Cisplatin forms DNA crosslinks in rapidly dividing tumour cells leading to apoptosis. At the same time it kills other normally dividing cells also and exerts toxic effects. Since proximal tubular cells are nondividing it is proposed that cisplatin nephrotoxicity takes place by different mechanism not by forming DNAadducts [7] rather by formation of nephrotoxins. In brief, cisplatin enters the cell by both active transport and passive diffusion; however, transportmediated uptake is the major intake mechanism in renal cells [3]. Two different membrane transporters have been identified which mediate in renal uptake of cisplatin, e.g., organic cation transporter 2 (OCT2) and copper transporter (Ctr1). Both OCT2 and Ctr1 are highly expressed in kidney and transport cisplatin in basolateral to apical direction [2,8]. Review Article Genetic Polymorphisms and CisplatinRelated Nephrotoxicity Arundhati Bag1*, Lalit Mohan Jeena2 and Niladri Bag3 1PhD, Assistant Professor, Department of Medical Biotechnology, Sikkim Manipal University, Sikkim 737102, India 2MSc, SRF, IVRI, Bareily, Uttar Pradesh, India 3PhD, Assistant Professor, Horticulture Department, Sikkim University, Sikkim 737102, India Dates: Received: 22 March, 2014; Accepted: 05 January, 2015; Published: 07 January, 2015 *Corresponding author: Dr. Arundhati Bag, PhD, Assistant Professor, Department of Medical Biotechnology, Sikkim Manipal University, Sikkim 737102, India, Tel: 08900528657; Email: [email protected]