235 - Correlation of c609t polymorphism of NADPH quinone oxidoreductase 1 and hematological toxicities in lung cancer patients treated with amrubicin

Date 28 September 2012
Event ESMO Congress 2012
Session Publication Only
Topics Lung and other Thoracic Tumours
Translational Research
Presenter Misato Nagata
Authors M. Nagata1, T. Kimura2, T. Suzumura3, S. Kudoh4, K. Umekawa1, Y. Kira5, K. Matsuura4, T. Nakai4, S. Mitsuoka4, K. Hirata4
  • 1Respiratory Medicine Dept., Osaka City University, 5458585 - Osaka/JP
  • 2Department Of Respiratory Medicine, Osaka City University, 5458585 - Osaka/JP
  • 3Cancer Center, Osaka City University, 5458585 - Osaka/JP
  • 4Respiratory Medicine, Osaka City University, 5458585 - Osaka/JP
  • 5Department Of Central Laboratory, Osaka City University, 545-8585 - Osaka/JP

Abstract

Background

Amrubicin hydrochloride (AMR) is a novel synthetic aminoanthracycline derivative, that is metabolically activated to amrubicinol (AMR-OH) by carbonyl reductase. The cytotoxic activity of AMR-OH is promising for small cell lung cancer and considered as a key agent. NADPH Quinone Oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes the quinone structures contained in both AMR and AMR-OH. NQO1 expression genotyped homozygous for minor alleles (T/T) was low compared with homozygous for major alleles (C/C) or heterozygous (C/T). We hypothesized that NQO1 C609T polymorphisms may relate to the AMR pharmacokinetics and clinical outcomes.

Methods

The patients with lung cancer received AMR at a dose of 30 or 40mg/m2/day on day 1-3 at Osaka City University Hospital were enrolled. Plasma sampling was performed at the time points of 24h after the third AMR injection. The concentrations of AMR and AMR-OH were determined by HPLC method. NQO1 C609T polymorphism was assayed using real-time polymerase chain reaction methods.

Results

A total of 35 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 40mg/m2 was administered to 16 patients. The mean plasma concentrations of AMR-OH on day4 at a dose of 30mg/m2 and 40mg/m2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (p = 0.005). In patients with AMR at a dose of 40mg/m2, the plasma concentrations of AMR-OH on day4 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 ± 4.47ng/ml (p = 0.066). The C/C was related to decrease changes in WBC, hemoglobin, and platelet counts (p = 0.01, p = 0.03, and p = 0.0005, respectively). No significant correlations were observed between NQO1 genotypes and clinical outcomes at a dose of 30mg/m2.

Conclusions

NQO1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities. NQO1 genotype appears to be the candidate biomarker of hematological toxicities of AMR treatment at a dose of 40mg/m2.

Disclosure

All authors have declared no conflicts of interest.