Approaches to multidrug resistance reversal.
Multidrug resistance (MDR) is characterised by cross-resistance between unrelated anticancer drugs and is associated with the overexpression of a membrane bound high-molecular weight glycoprotein, named P-glycoprotein, which is able to actively expel the drugs out of the cells. In vitro, numerous compounds have demonstrated the ability to inhibit the transport activity of P-glycoprotein, resulting in enhanced intracellular drug accumulation and MDR reversal. Such compounds include drugs of current use in other therapeutic areas, such as verapamil, cyclosporin A, quinidine or tamoxifen. Clinical trials have been performed on these drugs with the aim of reversing drug-resistance, but their toxicity was often too high. Therefore pharmaceutical firms have preferred to evaluate either analogues of these drugs, or compounds specifically designed for resistance reversal. Drugs that have clearly shown a potential for sensitisation of resistant cancers with acceptable toxicity include dexverapamil one of the two enantiomers constituting verapamil, valspodar (PSC-833), an analogue of cyclosporine A, and original compounds, named VX-710 and GF-120918. Positive results have most often been obtained in haematological malignancies (myelomas, lymphomas and acute myeloblastic leukaemias), but sometimes also in solid tumours (breast and ovarian carcinomas). Randomised Phase III studies are ongoing for compounds showing a definite activity in Phase II studies, with the aim of analysing the benefits of the combination of an MDR reverter and conventional chemotherapy, in terms of patients' survival. However, drug-resistance is a multifactorial phenomenon, with MDR constituting only part of it. In addition, a rigorous clinical evaluation of MDR will have to be performed, which has not always been the case in early trials.
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