Abstract
Studies described in the thesis that is lying in front of you aim to address the possible implications of selected ABC-drug transporters on the disposition of a number of important anticancer drugs. Although variability in drug disposition has been known for as long as pharmacological studies supported drug development and
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clinical therapeutics general molecular pharmacological concepts explaining the given interpatient variation in drug disposition have been lacking for many decades. Firm expansion on the knowledge of drug disposition was ignited by the discovery of the first identified drug transporter P-glycoprotein (Pgp; ABCB1), or permeability glycoprotein, in the hallmark publication of Juliano & Ling in 1976. They identified that this is a 170 kD transmembrane protein that, when expressed, enables cells to become resistant to a range of well known anticancer drugs. Later it was discovered that Pgp extrudes drugs from the inside of the cell to the extracellular compartment at the cost of ATP. Further studies identified that efflux by Pgp could be inhibited by verapamil, which would form the basis for the understanding of the concept of drug-drug interactions (DDIs) in vitro as well as in vivo mediated by Pgp and other later identified drug transporter proteins. This knowledge has translated in a first clinical trial aiming to overcome tumor unresponsiveness by co-administration of a Pgp inhibitor and a Pgp substrate drug doxorubicin, as it had been identified that a range of solid tumors and hematological malignancies expressed Pgp a possible cause of so-called multidrug resistance. Following this hallmark trial, improving this concept has been pursued in the laboratory and the clinic for a couple of decades. Despite the vast increase in knowledge of the family of drug transporters, the identification of a range of naturally occurring Pgp inhibiting substrate molecules and chemical synthesis of novel effective inhibitors clinical benefit of this concept turned out to be meager. Disappointingly, no combination of Pgp substrate anticancer drug plus Pgp inhibitor has shown a positive benefit/risk in pivotal studies and the concept has been abandoned almost completely for a number of reasons, of which discussion is considered beyond the scope of this introductory chapter as well as of this thesis as a whole. Knowledge of the field further deepened substantially by cloning and sequencing of the MDR (i.e. Multi Drug Resistance; ABCB family) gene encoding Pgp in 1986. Subsequently, identification of normal tissue expression of Pgp boosted research directed at unraveling the potential influence of Pgp on tissue distribution of affected substrate drugs. Discovery of another family of drug transporters, the Multidrug Resistance (-associated) Protein (MRP) family in 1992 was another important event further shaping the landscape of drug transporters. In the decade following this landmark discovery in the drug transporter field new families of drug transporters were identified and molecularly and pharmacologically characterized, including the Breast Cancer Resistance Protein (BCRP; ABCG2). The family members of the ABC-(i.e. ATP-Binding Cassette) drug transporters have now all been identified and for further details the reader is referred to recent reviews, including chapters two and three of this thesis, and websites, for example http://www.ncbi.nlm.nih.gov/books/ NBK31/ & http://www.genenames.org/. Besides discovery of all colors of the pallet of ABCdrug transporters valuable novel tools were established to enable studying the in vivo pharmacological effects of ABC-drug transporters of which the first one was the mdr1a Pgp knockout mouse.
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