Arch Pharm Res Vol 29, No 12, 1067-1073, 2006 ~rr of Ijarmaca[ ~e~eard~ http://apr.psk.or.kr Platinum Transporters and Drug Resistance Min-Koo Choi and Dae-Duk Kim Department of Pharmaceutic& College of Pharmacy, Seoul National University, Seoul 151-742, Korea (Received October 26, 2006) Cisplatin, a platinum coordinated complex, is a widely used antineoplastic agent for the treatment of metastatic tumors of the testis, metastatic ovarian tumors, lung cancer, advanced bladder cancer and many other solid tumors. The cytotoxic action of the drug is often thought to be associated with its ability to bind DNA to form cisplatin-DNA adducts. The development of resistance to cisplatin during treatment is common and constitutes a major obstacle to the cure of sensitive tumors. Although to understand the clinically relevant mechanisms of resistance, many studies have been aimed at clarifying the biochemical/molecular alterations of cisplatin-resistance cells, these studies did not conclusively identify the basis of cellular resistance to cisplatin. In this review, cisplatin resistance was discussed in terms of the relevant transporters, such as copper transporters (CTRs), organic cation transporters (OCTs) and multi-drug resistance related transporters (MDRs). These transporters seem to be contributed to cisplatin resistance through the reduction of drug accumulation in the cell. Better understanding the mechanism of cisplatin resistance associated with transporters will provide the useful informations for overcoming the cisplatin resistance. Key words: Cisplatin, Resistance, Transporters, CTRs, OCTs, MDRs INTRODUCTION Cisplatin has been recognized as an important antitumor agent since its introduction into clinical trials (Prestayko et al., 1979). It has been effective against several types of human malignancies including testicular, ovarian, cervical, bladder, head and neck, and small cell lung cancers. Particularly, about 80% of all patients with metastatic germ cell cancer will be cured after cisplatin-based combination chemotherapy (Kollmannsberger et al., 2006). However, many patients eventually relapse and develop resistance, representing a major limitation of cisplatin-based chemo- therapy (Giaccone, 2000). Two major strategies have been adopted to improve the efficacies of cisplatin-based chemotherapies: One is the development of platinum analogues with better therapeutic indices. Of these, carboplatin exhibits comparable efficacy and more favorable toxicity profiles than the first generation cisplatin (Lokich and Anderson, 1998). Third generation (e.g., Eloxatine | has been developed with the desire of finding new structures that show broad spectrum of Correspondence to: Dae-Duk Kim, Department of Pharmaceu- tics, College of Pharmacy, Seoul National University, Seoul 151- 742, Korea Tel: 82-2-880-7870, Fax: 82-2-873-9177 E-mail: ddkim@snu.ac.kr antitumor activity, lack of cross-resistance with cisplatin and carboplatin, and reduced toxicity (Weiss and Christian, 1993; Raymond et al., 2002). These developments have made platinum-based chemotherapy one of the most important treatments for human cancers. The other strategy is through better understanding the resistance mechanisms of cisplatin so that methods for circumventing drug resistance can be developed. Inside the cell, cisplatin forms intrastrand crosslink adducts on DNA, interferes with DNA synthesis and activates cell death pathways (Siddik, 2002, 2003). Thus, reduction in adduct formation (Fink et al., 1998) and enhanced repair of adducts (Johnson et al., 1997) have been suggested as important mechanisms of resistance. Another important issue relevant to the toxicity and resistance of cisplatin is transport system of cisplatin. In fact, defective uptake of cisplatin has been one of the most consistently identified characteristics of cells selected for cisplatin resistance both in vivo and in vitro (Anderson and Howell, 1990; Gately and Howell, 1993). Moreover, many reports point to reduced drug accumulation as a significant mechanism of cisplatin resistance (Ishida et al., 2002; Katano eta/., 2002). The intracellular concentration of cisplatin is a balance of uptake process into the cell and disposition process from the cell. Therefore, copper transporters are known to play an important role in the homeostasis of 1067