A149
Preclinical development of vorinostat for small cell lung cancer (SCLC)
Amanda Williamson1, Jian Mei Hou1, Emma Dean1, Paul Lorigan2, Caroline Dive1, Fiona Blackhall1
1Clinical and Experimental Pharmacology group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK, 2Cancer Research UK Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK
SCLC is highly chemosensitive but invariably relapses with chemoresistance. Chemo- and radioresistance can be associated with tumour hypoxia. The histone deacetylase inhibitors (HDIs), Trichostatin A and FR901228, cause growth arrest and induce apoptosis, respectively, in SCLC in vitro.Vorinostat was the first HDI approved by the FDA and preclinical studies suggest enhanced activity when Vorinostat is combined with other anticancer agents.
This study examined the effects of Vorinostat in a panel of SCLC cell lines in normoxic and hypoxic conditions. Vorinostat IC50 concentrations ranged from 8 to 28µM and were higher in hypoxic than normoxic conditions for 2 of 5 cell lines (IC50 values for H526 and H524 cells were 10µM/24µM and 28µM/33µM in normoxia/hypoxia respectively) as determined by the MTS assay. Preliminary studies demonstrate that in vorinostat treated samples there is down-regulation of anti-apoptotic Bcl-2, Mcl-1 and XIAP, with a corresponding increase in cleaved PARP suggesting the mechanism of reduced cell viability to be increased apoptosis. Moreover, Vorinostat was synergistic with either cisplatin or etoposide (eg Combination Index at IC50 dose for H526 cells = 0.9 and 0.649, respectively)as determined with Chou Talalay methodology.
Our data provide a rationale to evaluate vorinostat in combination withconventional chemotherapy (cisplatin and etoposide) among patients with SCLC. Ongoing experiments will examine the mechanism and timing of apoptosis in Vorinostat treated SCLC cell lines, and the scheduling of these agents in vitro to aid in determining the optimal clinical trial design.A phase I/II study is planned to commence later this year.
