As little progress has been made in the past decade, new strategies should meantime focus on targeting cancer cells at the molecular level. Recently, in a randomized phase III placebo-controlled trial, Moore et al demonstrated that combining gemcitabine with EGFR inhibitor erlotinib was associated with a modest, but statistically significant survival benefit of 15 d. In contrast, a recent phase III trial (SWOG S0205 study) failed to demonstrate a clinically significant advantage of the addition of cetuximab, an anti-EGFR monoclonal antibody, to gemcitabine for overall survival, progression free survival and response. Another approach is targeting VEGF as a key player in tumor growth and resistance to therapy. In a phase II trial with 52 patients, a combination of VEGF inhibitor bevacizumab and gemcitabine yielded a 21% response rate and a median survival of 8.
8 mo. These data led CALGB to conduct a randomized, double-blind, placebo-controlled, phase III trial (CALGB 80303). However, the addition of bevacizumab to gemcitabine did not improve survival. Inhibiting histone deacetylases (HDACs), which regulate interactions between histones and DNA together with histone acetylases (HATs) as counter-players, may be another promising molecular target. Clinical studies published so far have shown that HDAC inhibitors (HDACIs) can be administered safely in humans and that treatment of some cancers with such agents seems to be beneficial[12,13].
NVP-LAQ824 and NVP-LBH589 are new chemical entities belonging to a structurally novel class of cinnamic hydroxamic acid compounds[14�C17], which are currently in phase I clinical evaluation in advanced refractory solid tumors and hematologic malignancies[18�C22]. However, little is known Anacetrapib about their potential efficacy in pancreatic cancer. Therefore, the objectives of the current study were to investigate the efficacy of in vitro and in vivo treatment with the novel pan-HDAC inhibitors NVP-LAQ824 and NVP-LBH589 and to evaluate effects of combination with gemcitabine. MATERIALS AND METHODS Materials Eight human pancreatic cancer cell lines (Hs766T, As-PC-1, CFPAC-1, Capan-2, Panc-1, MiaPaca-2, HPAF-2 and L3.6pl) were examined[23�C27]. All cell lines were cultured in a 37��C incubator with 50-100 mL/L CO2 in appropriate media. The HDACIs NVP-LAQ824 and NVP-LBH589 were provided by Novartis (Basel, Switzerland) and dissolved in dimethyl sulfoxide (DMSO) (10 mmol/L stock).