Drug resistance is a major factor that limits the effectiveness of chemotherapy. Tumours can be intrinsically resistant prior to chemotherapy, or resistance may be acquired during treatment by tumours that are initially sensitive to chemotherapy [1]. Furthermore, in the process of acquiring resistance, the tumour may become cross-resistant to a range of chemotherapies and result in resistance, which ultimately leads to treatment failure in over 90% of patients with metastatic disease [2]. The problem of drug resistance is complex as numerous factors affect drug sensitivity, including: accelerated drug efflux; drug activation and inactivation; alterations in drug target; DNA methylation; processing of drug-induced damage; and evasion of apoptosis (Figure 1). Clearly, strategies to overcome chemoresistance are urgently needed. This article will provide an overview of tumour cell-specific drug resistance mechanisms and highlight examples that have clinical relevance. drug efflux

Increases in drug efflux are often responsible for enhanced drug resistance and are frequently due to enhanced expression of ATP binding cassette (ABC) transporter proteins, such as P-glycoprotein (Pgp)[3]. This type of resistance can affect a range of chemotherapies with differing mechanisms of action and is termed ‘multi-drug resistance’. It has most often been linked to overexpression of Pgp, which has been shown to be overexpressed in many drug-resistant cell lines as well as in a number of solid tumours [4, 5]. The cytotoxic drugs that are most frequently associated with multi-drug resistance are hydrophobic, amphipathic natural products, such as the taxanes, vinca alkaloids, anthracyclines and mitomycin C [5, 6]. Furthermore, the DNA topoisomerase-I inhibitor, irinotecan (CPT-11), and its active metabolite, 7-ethyl-10-hydroxycampothecin (SN-38), are targets for the ABC transporter proteins [4]. A cell line derived from human erythroleukaemia cells that was selected for resistance to the vinca alkaloid vincristine was found to overexpress Pgp and be cross-resistant to 5-fluorouracil (5-FU), suggesting that 5-FU may also be a target of Pgp [7]. Inhibiting Pgp as a strategy of reversing multi-drug resistance has been extensively studied for more than two decades. First generation Pgp inhibitors showed some initial success in the clinic. Chan and colleagues reported a high cure rate in retinoblastoma patients treated with cyclosporin A in combination with chemotherapy (relapse-free rate of 92% in