Drug transporters of platinum-based anticancer agents and their clinical significance
Introduction
Platinum-based drugs are among the most active anticancer agents and are used as single agent or in combination with other cytotoxic agents and/or radiation therapy in the management of a broad spectrum of human malignancies, including testicular, ovarian, head and neck, colon, bladder, gastric, and lung cancer (Ardizzoni et al., 2007, Go and Adjei, 1999, Lebwohl and Canetta, 1998, McWhinney et al., 2009, Raymond et al., 1998, Rixe et al., 1996, Zhang et al., 2006). Although most patients initially respond well to platinum-based chemotherapy, a considerable number of patients eventually develop drug resistance and relapse (Kollmannsberger et al., 2006). In spite of many efforts to circumvent platinum resistance and to reduce the toxicity of platinum-containing anticancer regimens, the development of either severe side effects, including nephro-, neuro- and ototoxicity, or clinical resistance, are frequent reasons for treatment discontinuation (Giaccone, 2000, McWhinney et al., 2009).
Platinum resistance is considered multi-factorial and includes both mechanisms that limit the formation of platinum–DNA adducts as well as mechanisms that prevent cell death following drug-induced damage (Table 1) (Shahzad et al., 2009, Brabec and Kasparkova, 2005, Stordal et al., 2007, Borst et al., 2008). Actually, reduced cellular accumulation of platinum either by impaired uptake or increased efflux is often found in cells selected for cisplatin resistance, both in vivo and in vitro, and is generally considered as one of the most consistent characteristics of platinum resistant cells (Gately and Howell, 1993).
Previously, passive diffusion through the cellular lipid bilayer was considered to be the dominant process involved in drug uptake and distribution. However, more recently the concept of carrier mediated and active uptake of commonly prescribed drugs, has become rule rather than exception (Dobson et al., 2009). Compelling evidence for a more prominent role of carrier-mediated uptake is rapidly cumulating in the literature (Dobson and Kell, 2008). Facilitated or active transport systems, as well as passive diffusion, are both relevant for the cellular uptake of platinum drugs (Andrews et al., 1990, Gately and Howell, 1993, Johnson et al., 1998). In addition general drug uptake/efflux systems in the intestine, liver and kidney are increasingly found to be important and may have a major impact on drug disposition and response to platinum-based chemotherapy (Terada and Inui, 2007). Thus, (membrane) transporters of platinum compounds, including solute carriers (SLCs) and in particular organic cation transporters (OCTs) belonging to the SLC22 subfamily, may at least in part, predict the platinum sensitivity/resistance of the tumour, markedly affect critical pharmacokinetic (PK) parameters, and determine the severity of platinum-associated adverse events.
Here we discuss the involvement of drug transporters in platinum uptake, efflux, distribution and (renal) elimination as well as their potential effect on treatment efficacy, on critical PK parameters and on the severity of platinum-associated adverse events. Finally, we assess the clinical relevance of platinum transporter-mediated drug–drug interactions.
Section snippets
Platinum compounds in clinical use
To date, three platinum drugs have been approved for clinical use, i.e. cisplatin (1978), its less toxic analogue carboplatin (1989) and oxaliplatin (2002). Various new generation platinum compounds with different properties have been developed over the years (Kelland, 2007a, Kelland, 2007b, Shah and Dizon, 2009). Some of these are currently evaluated in clinical trials. Especially, those with an improved safety profile, those exhibiting antitumor activity against tumour types resistant to
Platinum transporters and their potential effect on cellular accumulation and resistance
Membrane transporters and channels, collectively known as the transportome, are increasingly recognized as important determinants of tumour cell chemosensitivity and chemoresistance (Huang et al., 2004). Only a limited number of drug transporters, including both influx as well as efflux pumps, have been implicated in the intracellular accumulation of platinum compounds (Table 2) and reviewed by Choi and Kim (2006), Hall et al. (2008). Potential platinum uptake or influx transporters include
Transporter mediated drug–drug interactions and their potential effect on the PK of platinum compounds
Nowadays, polypharmacy is common clinical practice in cancer patients. Co-medication of drugs may influence each other's metabolism, excretion and uptake by so-called drug–drug interactions, which may lead to unintended effects like reduced effectiveness or increased toxicities. Transporter-mediated drug–drug interactions and their potential effects on the PK of anticancer drugs have lately been given particular attention (Kindla et al., 2009, Zhang et al., 2009). Clearly, substrate competition
Renal elimination of platinum compounds
It has been well established that most platinum compounds are predominantly eliminated from the body by glomerular filtration in the kidney. During their renal elimination, platinum drugs rely on active facilitated transport rather than passive diffusion across cellular membranes. The most relevant human platinum transporters known to date that are predominantly expressed in the kidney are SLC22A2 and SLC47A1/A2 (Koepsell et al., 2007, Terada and Inui, 2008). Renal tubular secretion of platinum
Platinum transporter-mediated side effects
The occurrence of adverse events from pharmacotherapy depends on many different factors including disease state, inherited disorders, PK characteristics of the drug, unintended drug–drug interactions, differences in drug metabolizing enzymes, transporter activity and renal clearance, and genomic variation in these absorption, disposition, metabolism and excretion (ADME) processes-associated genes. Serious side effects of anticancer platinum compounds have been reported and the possible
Future perspectives
Future developments in platinum-containing chemotherapeutic regimens will focus on novel delivery mechanisms with emphasis on improving the uptake and proper distribution of the existing platinum drugs by e.g. liposomal formulation of cisplatin-like drugs or by binding the platinum compounds to physiological (carrier) proteins to enhance their uptake. Knowledge of the involvement of platinum transporters may be exploited to develop appropriate intervention schedules. For instance, clinical
Acknowledgements
We gratefully thank Peter de Bruijn for preparing the chemical structures of the platinum compound using ChemWin as presented in Fig. 1.
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