Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer Szabolcs Modok, Howard R Mellor and Richard Callaghan Early publications using cultured cancer cells immediately recognized the phenomenon of resistance to anticancer agents. However, it was not until 1973 that it was first demonstrated that a major factor in the resistance of cancer cells was that of reduced drug accumulation. This year marks the 30th anniversary of the discovery by Juliano and Ling that P-glycoprotein mediates this active efflux of chemotherapeutic drugs from cancer cells. Since this seminal finding, the investigation of P-glycoprotein (MDR1, ATP binding cassette [ABC]B1) has proceeded with great vigour. However, it soon became apparent that P-glycoprotein was not expressed in all drug-resistant cells that displayed an accumulation deficiency, which led to the discovery of other ABC transporters involved in drug efflux. In 1992, the multidrug resistance-associated protein (MRP1, ABCC1) was identified in small cell lung cancer followed by breast cancer resistance protein (mitoxantrone resistance protein, ABCG2) in 1999. After three decades of research, can we confidently define the contribution of multidrug resistance transporters to chemoresistance and do we have clinically useful drugs to sensitise cancers? Addresses Oxford Drug Resistance Group, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK Corresponding author: Callaghan, Richard (richard.callaghan@ndcls.ox.ac.uk) Current Opinion in Pharmacology 2006, 6:350–354 This review comes from a themed issue on Cancer Edited by David Kerr and Mark Middleton Available online 11th May 2006 1471-4892/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2006.01.009 Introduction: the importance of multidrug efflux pumps in cancer Drug resistance in cancer comprises a network of con- tributing cellular and tissue factors. The phenotype denoted as multidrug resistance (MDR) is characterised by the contribution of drug efflux pumps such as P- glycoprotein (P-gp). P-gp confers resistance by prevent- ing sufficient accumulation of anticancer drugs within cells. The presence of multidrug efflux pumps in various types of cancer has been widely demonstrated. Often this expression is observed before chemotherapy and reflects the constitutive or ‘physiological’ expression in tissues such as the kidney, colon and liver. Expression is indu- cible by chemotherapy, with the most dramatic changes observed in leukaemia and breast cancer. Considerable effort has been directed towards correlating the expres- sion of multidrug pumps as an indicator of patient prog- nosis and the response to chemotherapy. Although a relationship between P-gp expression and drug resistance is widely accepted in leukaemia, the situation is less well- defined for solid tumours. The primary reason for the controversy stems from an abundance of clinical reports indicating that P-gp inhibitors often fail to restore che- motherapeutic efficacy in tumours expressing the trans- porter [1]. In an effort to resolve the disparity between in vitro evidence and clinical observations, many research teams have employed a battery of solid tumour or animal models. These studies provide convincing evidence that P-gp does affect the intracellular accumulation of drugs and also dictates their overall intra-tumour distribution [2]. Inter- estingly, the intra-tumour microenvironment (e.g. hypoxia and acidic pH) also greatly influences P-gp expression levels [3]. Moreover, the effect of P-gp on overall distribu- tion can be overcome pharmacologically in various tumour models and correlates with restoration of cytotoxic efficacy [4]. The lack of efficacy of pharmacological inhibitors in clinical studies has been attributed to numerous factors (see below) and has generated a certain degree of scepti- cism on the role of these drug transporters. In solid tumours, numerous factors account for the appar- ent lack of correlation between MDR and efflux pump expression. Often the trials have been poorly designed with regard to sample number, disease status or patient history (e.g. pre- or post-chemotherapy), leading to high sample variation. The type of analytical technique used to detect transporter expression (i.e. mRNA or protein) and the quality of available reagents also differed. The con- stitutive expression of multidrug efflux pumps in non- tumour tissue can also contaminate samples, leading to false interpretation of Western blot or mRNA expression results. In vivo functional imaging with Technecium probes [5] will be crucial in resolving the disputed role of multidrug efflux pumps in solid tumour resistance, particularly when correlated with clinical responses. Per- haps one of the simplest, yet oft ignored, factors is the multiplicity of drug resistance. Tumours are highly het- erogeneous and frequently develop multiple mechanisms of resistance, of which multidrug efflux pumps provide the first line of defence. Current Opinion in Pharmacology 2006, 6:350–354 www.sciencedirect.com