How to probe clinical tumour samples for p-glycoprotein and multidrug resistance-associated protein

Abstract

INTRODUCTION ONE FACTOR which supposedly limits the effectiveness of chemotherapy in cancer treatment is a reduced net uptake of cytostatic drug into the tumour cells, caused by the overexpression of plasma membrane drug transporters, leading to a multidrug resistant (MDR) phenotype. It has now been shown that two drug transporter proteins affect the net uptake of lipophilic natural product agents by human cancer cells. These proteins are P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). With the availability of gene probes and monoclonal antibodies against these proteins, the incidence of Pgp and MRP in clinical tumour specimens has been determined [l-4]. In general, results from many of the published studies on Pgp distribution in tissues and tumours are qualitatively quite similar, showing prominent Pgp expression in certain tissues (adrenal gland, liver, epithelium of gastrointestinal tract) and tumours (differentiated renal and colon cancers), but low, heterogeneous or undetectable Pgp in other tissues and tumours [l-3]. As far as MRP expression is concerned, the available probes and antibodies have been used to study its general distribution pattern [4-S]. However, what the quantitative role of Pgp (and MRP) is in clinical drug resistance is unknown, with current methodology giving irreproducible and inadequate answers [9-l 11. Possible reasons for this and possible improvements in MDR detection methodology are the topic of this paper.