Topoisomerase II and chemosensitivity for pegylated liposomal doxorubicin (pld) used in the third-line treatment of patients with metastatic bladder cancer.

Abstract

e15055 Background: PLD has been suggested to provide an option for advanced bladder cancer (Winquist et al., EJC, 2003; Vail et al., Sem Oncol, 2004). 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). Using tissue samples in selected patients, 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 tissues 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 42 patients, of which 19 tissue samples were available. Nineteen patients achieved a overall growth tumor control according to the RECIST assessment and 23 did not. Patients with disease control > 4 months 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 PLD for third-line advanced bladder cancer. Further investigations in larger patient materials are warranted.