piperidines and brivanib

Hepatocellular carcinoma (HCC) is one of the most common and challenging malignant disease. The prognosis is poor in patients with advanced disease. Although sorafenib prolongs survival in these patients, improvement remains modest. We used doxorubicin and sorafenib as controls and screened eight new agents including ixabepilone, gefitinib, cetuximab, brivanib, dasatinib, sunitinib, BMS-690514, and BMS-536924 against nine HCC cell lines and evaluated their interactions. We studied growth inhibition of 10 drugs against nine HCC cell lines. Single-agent activity was tested using an MTS assay. Combination studies were carried out in both resistant and sensitive cells to determine the combination index. The IC50 of each agent varied widely among nine cell lines. Ixabepilone was more potent than doxorubicin. HT-17 cells were more sensitive to gefitinib and cetuximab than the other eight cell lines. BMS-536924 showed good efficacy (IC50 ≤ 1 µmol/l) on all three α-fetoprotein (AFP)-producing cell lines (HepG2, Hep3B, Huh-7). Three cell lines showed moderate sensitivity to dasatinib (IC50 ≤ 1 µmol/l). Dasatinib showed the most frequent and strongest synergism with ixabepilone, gefitinib, brivanib, BMS-690514, or BMS-536924. Ixabepilone, sorafenib, brivanib, dasatinib, and BMS-536924 are active against HCC cell lines. The heterogeneity of the sensitivity of each cell line emphasizes the need for individualized treatment. The sensitivity to BMS-536924 is closely associated with the production of AFP. AFP may be a biomarker predicting response to the insulin-like growth factor-1 receptor inhibitor in HCC patients. Additional studies are warranted. The synergism between dasatinib and other agents also provides future research directions to understand drug resistance and improve outcome.

Topics: Alanine; alpha-Fetoproteins; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Hepatocellular; Cetuximab; Dasatinib; Doxorubicin; Drug Screening Assays, Antitumor; Epothilones; Gefitinib; Humans; Indoles; Inhibitory Concentration 50; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Pyridones; Pyrimidines; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Thiazoles; Triazines