ells like cancer cells. Both p53-dependent and independent routes of apoptosis activation are reported; necrotic-like cell death can also occur. Some tumors however, develop resistance while others may not respond to treatment. For instance, increased NER activity (repair rather than apoptosis) can lead to decreased sensitivity/increased resistance to drugs. Processes that affect the intracellular concentration of drugs can also contribute to drug sensitivity or resistance. In addition, the response can be toxic to non-cancer cells. The relative efficacy and/or toxicity as well as the molecular details of DNA lesions exhibited by the three drugs are different. Cisplatin appears to have the lead in terms of both potency and the toxicity of its side effects. Peripheral neurotoxicity, nephrotoxicity and ototoxicity are among the most severe cisplatin reported side effects. The cisplatin response pathway - the toxic effects of the drug and the drug are presented in this diagram; the pharmacokinetics/pharmacodynamics are presented in a related diagram. Once inside the cells, cisplatin becomes aquated by the gain of two molecules of water and as such is capable of interacting with nucleophilic molecules such as RNA, proteins, phospholipids and DNA, which is its primary target. Cisplatin promotes similar events in somatic, non-cancer cells as it does in cancer cells and exposure/accumulation due to increased expression of transporters, decreased expression of DNA repair genes, mutations or otherwise epigenetic or regulatory differences that render certain cells/tissues more prone to undergo apoptosis can underlie the toxic effects observed. Accumulation of cisplatin in the kidney, primarily in the tubules leads to impairment in proximal tubules, altered renal hemodynamics and is manifested in the acute and/or chronic nephrotoxic response. In the ear, cisplatin targets several areas in the cochlea including the hair cells in the organ of Corti which are the site of auditory mechanotransduction thus accounting for its ototoxic effect. The hearing loss associated with cisplatin treatment can lead to deafness and is particularly severe in young children. The incidence of ototoxicity, reported to be between 23-50% in adults, is greater than 50% in children. The neurotoxic effect includes symptoms such as numbness, distal paresthesias (tingling in extremities) and sensory ataxia. The mechanisms are not well understood but accumulation of cisplatin in dorsal root ganglia (DRG) may lead to the atrophy and/or loss of peripheral sensory neurons. Transporters whose expression is high in the cells of these tissues can play a role in the toxic effects associated with cisplatin treatment. The main influx cisplatin transporter is the high affinity copper transporter of the solute family 31 - Slc31a1, known as Ctr1. The transporter is highly expressed in the kidney and is also found in several cochlear structures including the organ of Corti. Ctr1 mRNA has been found in rat DRG and the expression of Ctr protein was found in a subpopulation of large-size DRG neurons that became atrophied upon cisplatin treatment. Thus, Ctr1 which is critical for the cisplatin tumor response, can also be responsible for its toxic effects. The members of the Slc22A family include organic cation (OCTs), organic cation/carnitine (OCTNs) and organic anion transporters (OATs). Of the three OCT genes, the OCT2 is highly expressed in the kidney; uptake of cisplatin in cells transfected with human Oct2 induced apoptosis; the involvement of Oct2 in renal cisplatin toxicity is also evidenced in studies using animal models. Oct2 is also expressed in the cochlea and deletion of this gene protected mice from ototoxicity. Slc47a1, known as Mate1 is a member of the multidrug and toxin extrusion transporter Slc47 family; it is expressed in the kidney and may mediate the renal efflux of cisplatin. The nephrotoxicity of cisplatin was increased in a mouse Mate1 null compared to the wild type and the renal accumulation of cisplatin was also significantly higher. In rat DRG, the expression of Slc22a4/Octn1 and Slc22a5/Octn2 is observed and cells overexpressing the rat and human genes can mediate platinum derivatives uptake, although Octn1 may be the main carrier. Thus, Slc31a1/Ctr1 is possibly implicated in all three toxic effects of cisplatin, Slc22a2/Oct2 may play a role in nephrotoxicity and ototoxicity, Slc47a1/Mate1 in nephrotoxicity and Slc22a4/Octn1 in neurotoxicity. To see the ontology report for annotations, Gviewer and download, click here...(less)