Topoisomerase II, carbonyl reductase I, and chemosensitivity for amrubicin in the treatment of patients with small-cell lung cancer

Abstract

8104 Background: Amrubicin (AMR) has been suggested to provide a new effective therapeutic option for small-cell lung cancer (SCLC). It is a totally synthetic 9-aminoanthracyclin and converted by carbonyl reductase I (CBR-I) to its active form, amrubicinol, that has higher potent activity than the parent drug and inhibits purified human topoisomerase II (topo-II). We previously reported the promising result of a prospective phase II trial for AMR monotherapy in patients with second-line SCLC (Thoracic Oncology Research Group Study 0301). Using blood samples at enrollment in this trial, the clinical significance of topo-II and CBR-I expression levels on antitumor effect as well as toxicity has been examined. Methods: Total RNA was extracted from the blood with an RNeasy Mini Kit (Qiagen Inc.) and DNase treatment was performed using the RNase-Free DNase Set (Qiagen Inc.). RT-PCR analysis was performed using TaqMan technology. Quantification of target cDNA (Top-II alpha, CBR-I and beta-actin gene) was conducted using an ABI PRISM 7700 Sequence Detection System (Applied Biosystems Inc.). Quantification was performed using the relative standard curve method. Results: The trial registered a total of 60 patients, of which 40 blood samples were available. Nineteen patients achieved a CR or PR to AMR according to the RECIST assessment and 21 did not. Patients with tumor response had a significantly lower Topo-II level than those without (p=0.0465, Wilcoxon test), although there was no association between tumor response and the level of CBR-I (p=0.3229, Wilcoxon test). We did not find any significant association between the levels of the two enzymes and toxicity. Conclusions: Topo-II may be a potential predictor of response in the treatment of AMR for second-line SCLC. Further investigations in larger patient materials are warranted. No significant financial relationships to disclose.