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Symposium 31: ABC Transporters and Cancer Biology and Treatment

ABC transporters and cancer treatment

The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Abstract

SY31-4

Clinical application of a broad range of structurally unrelated anticancer drugs is limited by low and variable oral uptake and low tissue distribution. This is caused by active efflux of these drugs mediated by membrane transporters of the ATP-binding cassette (ABC) superfamily, which have now been subdivided into seven families designated A through G. The first of the ABC drug transporters discovered was the 170 kDa P-glycoprotein (P-gp, MDR1, ABCB1), which expression in tumor cells converted these cells multidrug resistant (MDR). P-gp is mainly present in epithelial cells in the body, where it is localized in the apical membrane. P-gp transports substrates from the basolateral to the apical side of the epithelium in an active ATP-dependent manner, which takes place against a concentration gradient. P-gp has broad substrate specificity, most of the efficiently transported molecules being hydrophobic, amphiphilic in nature. Active drug transport by P-gp has significant and sometimes even clinically important consequences for the affected substrate drugs, for example paclitaxel, docetaxel, the vinca alkaloids and anthracyclines. The observation that the calcium channel blocker verapamil inhibited drug efflux and restored drug sensitivity in multidrug resistant leukaemia cell lines has resulted in clinical trials with verapamil and other P-gp inhibitors in combination with affected anticancer agents to reverse P-gp-mediated MDR in patients. This concept initiated the development of more potent second and more selective third generation P-gp inhibitors. Unfortunately, the results to overcome MDR in cancer patients by concomitant use of any of these P-gp inhibitors were disappointing. Interestingly, later insights indicated that such inhibitors could be used to modulate pharmacological properties of P-gp substrate drugs, resulting in improved oral bioavailability and passage across the blood-brain barrier. This was based on the high expression of P-gp not only in tumor tissues, but also in normal tissues including the apical membrane of small and large intestinal epithelium and in endothelial cells at the blood-brain barrier. Improvement of the bioavailability of anticancer drugs enables oral dosing, which is more practical and convenient to patients and which enables chronic treatment. Improvement of brain penetration is desirable to increase the uptake of anticancer agents into brain tumors (e.g., glioblastomas) or brain metastases, which are positioned behind a proficient blood-brain barrier. Besides P-gp, the Multidrug Resistance Proteins 1–5 (MRP1–5, ABCC1–5), and Breast Cancer Resistance Protein (BCRP, MXR, ABCG2) have a role in the transport of anticancer drugs. In addition, also MRP1, MRP2, MRP4, and BCRP have recently been shown to play a critical role in the blood-brain barrier by limiting the brain penetration of substrate drugs. Proof of concept studies with oral paclitaxel in patients combined with the P-gp inhibitor cyclosporin A (CsA) have clearly shown that the systemic exposure to paclitaxel can significantly be improved (1). Phase II studies with this combination in NSCLC, breast and gastric cancer have demonstrated high activity and excellent safety of this treatment (2). BCRP is also localized in the apical cellular membrane and is able to efficiently extrude drug substrates from the cell. BCRP is expressed in a variety of normal tissues with highest levels found in the placenta and lower levels in liver, small intestine, brain, and ducts and lobules of the breast. The tissue distribution of BCRP shows significant overlap with that of P-gp, suggesting that BCRP might have a similar role as P-gp in the pharmacological handling of substrate drugs. BCRP could potentially affect oral absorption, tissue distribution, and/or hepatobiliary and intestinal elimination of xenobiotics and/or their metabolites that are substrate of the protein. Furthermore, BCRP may be relevant in protecting the fetus from drug accumulation, because of its relatively high expression in placenta. BCRP may also play an important role in the blood-brain barrier. Topotecan is efficiently transported by BCRP and has a low affinity for P-gp. In a clinical study, oral topotecan revealed low bioavailability and moderate interpatient variability [30 ± 7.7% (range 21–45%)]. In a clinical proof of concept study it was shown that the apparent bioavailability of topotecan could be increased by co-administration of the P-gp and BCRP inhibitor elacridar from 40% without to complete bioavailability (97%) with elacridar (3). This concept is now ready for testing in pivotal trials, for example in advanced ovarian cancer. Current trials also explore improvement of accumulation of anticancer drugs into the brain by co-administration of a P-gp and/or BCRP inhibitor, for example paclitaxel plus elacridar in the treatment of glioblastoma. Patients treated with paclitaxel, docetaxel or topotecan may benefit from the outlined strategies and receive oral treatment. Furthermore, these concepts may also serve as a template for the oral development of other anticancer agents that need to be given on a chronic basis and that show low and variable oral bioavailability caused by affinity for ABC transporters.