Recent Pharmacological Advances: Focus on Small-cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) represents approximately 15% of all lung cancers, and is the most aggressive form of lung cancer. Left untreated, the time from diagnosis to death is 2-3 months. With current treatment, expected survival is 7-20 months, depending on the stage of disease. A new drug, amrubicin, is approved in Japan for lung cancer and has demonstrated efficacy in U.S. and European phase II trials of SCLC patients with either untreated disease or relapsed refractory illness. In a phase II study of amrubicin in previously untreated patients, response rates reached 75% with a median survival time of almost 1 year. Amrubicin is a fully synthetic 9-aminoanthracycline, and an analog of doxorubicin and epirubicin. The major mechanism of action of amrubicin is inhibition of topoisomerase II. Unlike doxorubicin, however, it exhibits little or no cardiotoxicity in clinical studies and preclinical models. In preclinical rodent tumor models, it is selectively distributed to tumour tissue and is not detected in the heart when compared with doxorubicin, which is distributed equivalently to these sites. The primary metabolite of amrubicin, amrubicinol, is up to 100 times more cytotoxic in vitro than the parent compound. This review describes the mechanisms of action of amrubicin as well as clinical studies which demonstrate the potential of this drug in future SCLC treatment. The review also puts forward hypothetical considerations for the use of other drugs such as lenalidomide, an immunomodulatory drug acting on multiple signalling pathways, or histone deacetylase inhibitors, in combination with amrubicin in SCLC.

Increased cellular accumulation and distribution of amrubicin contribute to its activity in anthracycline-resistant cancer cells

“…Amrubicin is metabolized to amrubicinol, which is approximately 100-fold more potent than amrubicin and has enhanced topoisomerase (topo)-II inhibitory activity. Clinically achievable plasma levels of amrubicin and amrubicinol are 20 and 2 lM, respectively, with halflife values of 17.6-24.5 h and 4-7 h, respectively [7,8].…”