Amrubicin hydrochloride (AMR) is a novel synthetic aminoanthracycline derivative. AMR is metabolized to amrubicinol (AMR-OH), and the cytotoxic activity of AMR-OH is 18–220 times more potent than that of AMR. NADPH quinone oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes the quinone structures which are contained in both AMR and AMR-OH. Recent report showed that C609T polymorphisms of NQO1 had a significant inverse correlation with in vitro AMR-OH cytotoxicity. Previously, we reported that the plasma concentration of AMR-OH on day 4 is correlated with hematological toxicities (anti-cancer drugs 2009). We hypothesized that the C609T polymorphisms of NQO1 may relate to the AMR-OH plasma concentrations and clinical outcomes. To test this hypothesis, a pharmacogenomics study was carried out on patients with lung cancer received AMR at a dose of 30 or 40 mg/m2/day on days 1–3. Plasma sampling was carried out at the time points of 24 h after the third AMR injection (AMR on day 4 and AMR-OH on day 4).Methods
The concentrations of AMR and AMR-OH were determined by the HPLC method. DNA was isolated from blood and C609T was assayed using RT–PCR.Results
Thirty-five patients were enrolled. The C/C, C/T and T/T were observed in 12 (34.3%), 16 (45.7%) and 7 (20%) patients, respectively. A dose of 30 mg/m2 was administered to 19 patients, and 40 mg/m2 was administered to 16 patients. The mean plasma concentrations of AMR-OH on day 4 at a dose of 30 and 40 mg/m2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (P = 0.005). No significant correlations were observed between NQO1 genotypes and clinical outcomes in patients with AMR at a dose of 30 mg/m2. In patients with AMR at a dose of 40 mg/m2, the plasma concentrations of AMR-OH on day 4 exhibited a tendency toward a relationship with NQO1 genotypes with values of C/C 20.5 ± 5.89, C/T 15.9 ± 5.43 and T/T 11.2 ± 4.47 ng/ml (P = 0.066). The significant relations were observed between NQO1 genotypes and decrease percentage changes in WBC, hemoglobin and platelet counts (P = 0.01, 0.03 and 0.0005, respectively).Conclusions
The NQO1 genotype appears to be the candidate biomarker of hematological toxicities of AMR treatment at a dose of 40 mg/m2.