Multidrug resistance: clinical relevance in solid tumours and strategies for circumvention

Abstract

Strictly speaking, multidrug resistance (MDR) describes the experimental observation of cross resistance to various structurally unrelated cytotoxic agents in laboratory models of cancer. These drugs have in common their origin as natural products, and in 1985 the basis of this MDR was established as the over-expression of a membrane glycoprotein, called P-glycoprotein (Pgp), which acts as a drug efflux pump actively depleting intracellular drug concentrations in resistant tumour cells. Since then, MDR has arguably taken on a second meaning, i.e. 'misunderstood drug resistance', through the understandable, but mistaken assumption by many scientists and some clinicians that the clinical observation in cancer patients treated with chemotherapy of resistance to a wide range of cytotoxic drugs (either as a primary or acquired property) inevitably involves the same mechanism. At present, the evidence from clinical studies to support such a notion is clearly lacking, particularly in solid tumours. However, increased Pgp expression has been observed in a number of clinical situations, and its relevance requires further elucidation. Current data indicate that increased Pgp expression represents an adverse prognostic factor, for reasons which may be quite unrelated to developing drug resistance. Experimentally, MDR can be reversed by simultaneous treatment with a number of non-cytotoxic agents which competitively inhibit Pgp function. Despite the reservations outlined, numerous clinical trials of this approach have been conducted. The results have generally been negative in solid tumours, although some have been more promising in haematological cancers. The most recent studies have used more potent modulating agents, such as the cyclosporin analogue, PSC833. Interpretation of data from these trials is complicated by pharmacokinetic interactions between the target cytotoxic drug and the modulating agent. Randomized trials are now underway in a number of tumour types; thus a clearer picture of the clinical relevance of MDR should emerge over the next few years.