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Membrane Transport - Biology and Therapeutics' and BACR Members' Proffered Papers '." Macmillan Press 1994 Br. J. Cancer (1994), 69, 1184-1197 © Macmillan Press Ltd., 1994 MEETING REPORT British Association for Cancer Research/Association of Cancer Physicians/Society for Drug Research Joint Symposium on 'Membrane Transport - Biology and Therapeutics' and BACR Members' Proffered Papers Held at Brian Drewe Lecture Theatre, Charing Cross & Westminister Medical School, The Reynolds Building, St Dunstan's Road, Hammersmith, London W6 8RP, UK on 13/14 December 1993. Abstracts of invited papers The ABC superfamily of membrane transporters in human tumors. The multidrug resistance phenotype is associated with the overproduction of P-glycoprotein, an C.F. Higgins integral membrane phosphoprotein that acts as an energy- dependent drug efflux pump with a broad specificity for Imperial Cancer Research Fund, Institute of Molecular hydrophobic antitumor drugs. Each half of P-glycoprotein is Medicine, University of Oxford, John Radcliffe Hospital, designated as a cassette that contains six putative transmem- Oxford OX3 9DU, UK. brane domains. Each cassette is followed by a nucleotide binding domain and the two cassettes are joined by a linker The human multidrug resistance P-glycoprotein is a member region. The use of '25I-iodoarylazidoprazosin and 3H-azi- of the ABC superfamily of membrane transporters. Over 50 dopine, two photoaffinity probes that bind specifically to members of this superfamily have now been identified, in p-glycoprotein, and immunological mapping methods have species including bacteria, yeasts, plants, insects and mam- located major photolabelled drug binding domains in each mals. These transporters are associated with a wide variety of cassette, immediately C-terminal to TM6 and TM12. biological processes and, in man, several are associated with A combination of cyanogen bromide digestion and clinical disorders. An overview of the structure and function immunoblot analysis has been usd to domain map the phos- of ABC transporters will be presented. phorylation sites in p-glycoprotein. The majority of phos- The human multidrug resistance P-glycoprotein will be phorylation occurs within a single cyanogen bromide frag- discussed in detail, particularly its apparent relationship to ment (amino acids 627-682) that encompasses the majority the cystic fibrosis gene product CFTR. P-glycoprotein con- of the linker region. Our studies indicate that in vitro protein fers resistance of cancers to chemotherapy, pumping hydro- kinase C and protein kinase A phosphorylation occurs at phobic drugs from cells using the energy of ATP hydrolysis. serines 669 and 681, respectively. The effects of phosphoryla- Recently, P-glycoprotein has also been shown to be associ- tion on p-glycoprotein function are being evaluated. ated with a chloride channel activity, although it is not known whether P-glycoprotein is the channel or simply a channel regulator. This chloride channel activity may reflect a physiological role for this protein in regulating epithelial Multidrug resistance, drug accumulation and intra-celHular cell volume. The possibility that P-glycoprotein is bifunc- drug distribution tional, associated with both active transport and channel functions has general important implications for the distinc- H.J. Broxterman, G.J. Schuurhuis, C.H.M. Versantvoort, tion between channels and transporters. In particular, this H.M. Pinedo & J. Lankelma finding has implications for the development of drugs which inhibit P-glycoprotein and reverse multidrug resistance. The Department of Medical Oncology, Free University Hospital, de effect of inhibitors on the channel and transporter functions Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. associated with P-glycoprotein will be discussed. Multidrug resistance refers to the type of resistance to cyto- Valverde, M.A. & others (1992). Nature, 355, 830-833. static drugs with different chemical structures and different Gill, D.R. & others (1992). Cell, 71, 23-32. cellular targets caused by mechanisms that result in a Trezise, A.E.O. & others (1992). EMBO J., 11, 4291-4303. decreased concentration of drugs at the target sites. ATP Higgins, C.F. (1992). Ann. Rev. Cell. Biol., 8, 67-113. dependent drug transporters have been identified recently in mammalian cells, including human cancer cells. Upregulation of such drug transporter activity frequently occurs upon in vitro selection of tumor cell lines with cytostatic drugs. Murine P-glycoprotein: identification of drug binding and I will discuss data from our laboratory on daunorubicin phosphorylation sites (DNR) transport by three drug transporters: P-glycoprotein (Pgp), 'GLC4/ADR' type (small cell lung cancer) and 'SW- S.B. Horwitz 1573/2R120' type (non-small cell lung cancer). Evidence for active drug transport in these systems is: (a) DNR (and Department of Molecular Pharmacology, Albert Einstein VP-16) efflux is ATP-dependent; (b) DNR efflux is against a College of Medicine, Bronx, NY 10461, USA. concentration gradient; (c) upon permeabilization of the plasma membrane with low digitonin concentrations there is Drug resistance constitutes a major problem in the treatment DNR net influx, showing that the cytoplasmic drug concent- of human malignancies. Evidence is accumulating that multi- ration is kept below the extracellular concentration. Further- drug resistance is one form of drug resistance that has a role more, differences in passive drug permeation (passive JOINT WINTER MEETING REPORT 1185 permeation coefficient), intracellular pH or DNA content clinical pharmacology of these complex drug interactions is could not explain the DNR accumulation defects. being defined. Additional evidence for presence of a drug transporter is the saturability of the active DNR transport; assuming sim- Yahanda, A.M. & others (1992). J. Clin. Oncol., 10, 1624-1634. ple Michaelis-Menten kinetics and no preference for neutral Lum, B.L. & others (1992). J. Clin. Oncol., 10, 1635-1642. DNR transport by the pump we could calculate an apparent Sikic, B.I. (1993). J. Clin. Oncol., 11, 1629-1635. Km of 1.5 tLM for DNR transport by Pgp as well as the 'GLC4/ADR' transporter. A further characteristic of drug transporters is the pos- sibility to inhibit DNR transport by agents that compete for the drug interaction with the transporter. An example will be shown of the competitive interaction of the isoflavonoid The Gordon Hamilton-Fairley Memorial Lecture genistein with the 'GLC4/ADR' transporter. Another characteristic of many MDR cells is the relatively Multidrug resistance: friend or foe? more decreased accumulation of anthracyclines in the nucleus (N), compared to the cytoplasm (C), leading to e.g. a lower M.M. Gottesman doxorubicin fluorescence N/C ratio in MDR compared to sensitive cells. A decrease in drug accumulation plus altered Laboratory of Cell Biology, National Cancer Institute, National drug distribution in many cases may explain the resistance in Institutes of Health, Bethesda, Maryland 20892, USA. (Pgp)/MDR cells. Also this method can be used to screen for an MDR phenotype in individual cells, e.g. in human acute The cloning of a cDNA for the human MDR1 gene, and the myeloid leukemic blasts, using fluorescence microscopy. demonstration that expression vectors encoding the multi- We conclude that future efforts to identify functional drug drug transporter (P-glycoprotein) could confer multidrug transporters, together with gene-specific (MDRI, MRP ...?) resistance on sensitive cells, made possible the use of these analysis of tumors would lead to a better insight of cellular vectors for human gene therapy. Two possible approaches MDR and possibilities to reverse specifically these types of can be considered: (1) use of MDR1 expression vectors to resistance. confer multidrug resistance on tissues normally susceptible to the toxic effects of chemotherapy, especially bone marrow; and (2) use of MDR1 expression vectors which also encode otherwise non-selectable genes so that selection for multidrug resistance results in expression of these non-selectable Clinical trials of modulation of multidrug resistance markers. The advantages of using the MDR1 cDNA for such studies include the broad spectrum of drug resistance encod- B.I. Sikic ed by this cDNA, the surface localization of P-glycoprotein allowing for easy detection and sorting, and the ability to Oncology Division, Stanford University School of Medicine, create 'designer' MDR1 vectors with substrate and inhibitor Stanford, California 94305-5306, USA. specificities which are distinct from the endogenous MDR1 gene. Using retroviral vectors, the human MDR1 cDNA has Multidrug resistance (MDR), mediated by P-glycoprotein (P- been successfully transferred into mouse bone marrow, where gp) and encoded by the mdrl gene, is one of the best it confers resistance to taxol and daunorubicin in vivo. Three understood mechanisms of resistance to anticancer drugs. A clinical trials in which a human MDR1 cDNA will be trans- growing body of evidence indicates that expression of mdrl duced into bone marrow of patients undergoing autologous contributes to clinical resistance to chemotherapy. P-gp in bone marrow transplantation for brain tumors and cancers normal tissues may be important in the excretion of MDR- of the ovary and breast have recently been approved by the related anticancer agents as well as many other drugs. Recombinant Advisory Committee in the US. We are also Several clinical trials have attempted to modulate MDR by developing vectors which utilize the MDR1 gene to select for co-administration
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