Cellular mechanisms of resistance in CML include point mutations in BCR-ABL gene (up to 40 identified), BCR-ABL amplification selleck chemicals or activation of alternative survival signalling pathways (Sawyers et al, 2002; Weisberg and Griffin, 2003). For GISTs, the tumour genotype is a predictor of response to imatinib. Patients harbouring tumours characterised by an exon 11 KIT mutation may benefit from a better response to imatinib compared to other subgroups, notably exon 9 mutants or wt KIT tumours (Heinrich et al, 2003; Debiec-Rychter et al, 2006). Molecular analysis of GISTs thus appears to be an important clinical tool to identify patients at high risk of disease progression. Moreover, about half of the imatinib-resistant GIST patients had acquired secondary mutations in the kinase domain of c-KIT (Antonescu et al, 2005).

Additionally, resistance could also be directly or indirectly caused by an increase in cellular efflux of imatinib, mediated mainly by the drug transporter P-gp (P-glycoprotein) (Mahon et al, 2003; Widmer et al, 2007), or by a decrease in cellular influx, mediated by the uptake carrier hOCT1 (organic cation transporter) (Thomas et al, 2004; Crossman et al, 2005; Wang et al, 2008). Host-dependent mechanisms of resistance have also been incriminated, including modulation of imatinib binding to ��1-acid glycoprotein (AGP) in plasma (Gambacorti-Passerini et al, 2000; Gambacorti-Passerini et al, 2003; Larghero et al, 2003) and/or possibly enhanced drug metabolism (Rochat et al, 2008). Finally, nonadherence to imatinib dosage regimen may also play a role in resistance (Tsang et al, 2006).

A given dose therefore yields very different circulating concentrations between patients (Widmer et al, 2006; Larson et al, 2008), possibly favouring the selection of resistant cellular clones in case of subtherapeutic drug exposure. Several pharmacokinetic (PK) studies have been carried out for imatinib. Some have been able to verify the influence of factors such as weight, albuminaemia, haemoglobinaemia or ABCB1 (MDR1) polymorphism on its PK (Judson et al, 2005; Schmidli et al, 2005; Gurney et al, 2007) but not of those such as hepatic enzymes or impaired liver or kidney function (Widmer et al, 2006; Gibbons et al, 2008; Ramanathan et al, 2008).

Furthermore, recent evidence suggests that steady-state trough imatinib plasma concentration (TPC) at initiation of therapy is a significant predictor of complete cytogenetic and major molecular responses (Larson et al, 2008). TPC also appears to correlate with response in CML (Picard et al, 2007) as well Brefeldin_A as in GIST (Demetri et al, 2008). Interestingly, recent studies have begun to investigate the free drug exposure of imatinib (Delbaldo et al, 2006; Widmer et al, 2006). The study from Delbado also explored the relationship between drug exposure (area under the curve, AUC) and effect.