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Multidrug resistance: clinical relevance in solid tumours and strategies for circumvention
1CRC Department of Medical Oncology, University of Glasgow, Bearsden, UK.
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.
Insights
Multidrug resistance (MDR) in cancer is often misunderstood. While P-glycoprotein (Pgp) causes experimental MDR, its clinical role is unclear, and Pgp inhibitors show limited success in solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) experimentally arises from P-glycoprotein (Pgp) over-expression, acting as a drug efflux pump.
- Clinical MDR is often assumed to involve Pgp, but evidence in solid tumors is lacking.
- Increased Pgp expression may be a negative prognostic factor unrelated to drug resistance.
Purpose of the Study:
- To clarify the clinical relevance of P-glycoprotein (Pgp) in multidrug resistance (MDR).
- To evaluate the efficacy of Pgp inhibitors in reversing MDR in cancer patients.
- To differentiate experimental MDR from clinical observations of drug resistance.
Main Methods:
- Review of experimental data on Pgp-mediated MDR.
- Analysis of clinical trial results using Pgp inhibitors.
- Investigation of Pgp expression in various cancer types.
Main Results:
- Experimental MDR is linked to Pgp efflux pump activity.
- Clinical evidence for Pgp-driven MDR in solid tumors is limited.
- Pgp inhibitors have shown limited efficacy in solid tumors but some promise in hematological cancers.
- Increased Pgp expression is associated with poorer prognosis, potentially independent of drug resistance.
Conclusions:
- The clinical significance of Pgp in MDR remains uncertain, especially in solid tumors.
- Pgp inhibitors have not consistently reversed clinical drug resistance.
- Further randomized trials are needed to elucidate the role of Pgp and MDR in cancer treatment outcomes.