Drug transporters of platinum-based anticancer agents and their clinical significance.
Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. However, acquired and/or intrinsic resistance still represent a major limitation. Lately, in particular mechanisms leading to impaired uptake and/or decreased cellular accumulation of platinum compounds have attracted attention. In this review, we focus on the role of active platinum uptake and efflux systems as determinants of platinum sensitivity and -resistance and their contribution to platinum pharmacokinetics (PK) and pharmacodynamics (PD). First, the three mostly used platinum-based anticancer agents as well as the most promising novel platinum compounds in development are put into clinical perspective. Next, we describe the presently known potential platinum transporters--with special emphasis on organic cation transporters (OCTs)--and discuss their role on clinical outcome (i.e. efficacy and adverse events) of platinum-based chemotherapy. In addition, transporter-mediated tumour resistance, the impact of potential platinum transporter-mediated drug-drug interactions, and the role of drug transporters in the renal elimination of platinum compounds are discussed.
Department of Medical Oncology, Erasmus Medical Center Rotterdam-Josephine Nefkens Institute and Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. h.burger@erasmusmc.nl
Herman
H
Burger
Walter J
WJ
Loos
Karel
K
Eechoute
Jaap
J
Verweij
Ron H J
RH
Mathijssen
Erik A C
EA
Wiemer
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D016190:Carboplatin / Q000493:pharmacokinetics / Q000494:pharmacology; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077150:Oxaliplatin
D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin