Andreas P. Sutter

Targeting the epidermal growth factor receptor by erlotinib (Tarceva) for the treatment of esophageal cancer.

Esophageal cancer is the sixth most common cause of cancer‐related death worldwide. Because of very poor 5‐year survival new therapeutic approaches are mandatory. Erlotinib (Tarceva™), an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR‐TK), potently suppresses the growth of various tumors but its effect on esophageal carcinoma, known to express EGFR, remains unexplored. We therefore studied the antineoplastic potency of erlotinib in human esophageal cancer cells. Erlotinib induced growth inhibition of the human esophageal squamous cell carcinoma (ESCC) cell lines Kyse‐30, Kyse‐70 and Kyse‐140, and the esophageal adenocarcinoma cell line OE‐33, as well as of primary cell cultures of human esophageal cancers. Combining erlotinib with the EGFR‐receptor antibody cetuximab, the insulin‐like growth factor receptor tyrosine kinase inhibitor tyrphostin AG1024, or the 3‐hydroxy‐3‐methylglutaryl coenzyme. A reductase (HMG‐CoAR) inhibitor fluvastatin resulted in additive or even synergistic antiproliferative effects. Erlotinib induced cell cycle arrest at the G1/S checkpoint. The erlotinib‐mediated signaling involved the inactivation of EGFR‐TK and ERK1/2, the upregulation of the cyclin‐dependent kinase inhibitors p21Waf1/CIP1 and p27Kip1, and the downregulation of the cell cycle promoter cyclin D1. However, erlotinib did not induce immediate cytotoxicity or apoptosis in esophageal cancer cells. The inhibition of EGFR‐TK by erlotinib appears to be a promising novel approach for innovative treatment strategies of esophageal cancer, as it powerfully induced growth inhibition and cell cycle arrest in human esophageal cancer cells and enhanced the antineoplastic effects of other targeted agents.

A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

BackgroundTherapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferon-γ (IFNγ) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells.Methods and resultsIFNγ receptors were expressed in both models. IFNγ dose- and time-dependently inhibited the growth of both STC-1 and of BON tumor cells with IC50-values of 95 ± 15 U/ml and 135 ± 10 U/ml, respectively. Above 10 U/ml IFNγ induced apoptosis-specific caspase-3 activity in a time-dependent manner in either cell line and caused a dose-dependent arrest in the S-phase of the cell cycle. Furthermore, IFNγ induced cytotoxic effects in NE tumor cells.The NE tumor-targeted drug MIBG is selectively taken up via norepinephrine transporters, thereby specifically inhibiting growth in NE tumor cells. Intriguingly, IFNγ treatment induced an upregulation of norepinephrine transporter expression in neuroendocrine tumors cells, as determined by semi-quantitative RT-PCR. Co-application of sub-IC50 concentrations of IFNγ and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle.ConclusionOur data show that IFNγ exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNγ with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNγ alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors.

Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human esophageal cancer cells

Esophageal cancer is the most markedly increasing tumor entity in Western countries. Due to very poor 5-year-survival, new therapeutic approaches are mandatory. Peripheral benzodiazepine receptors (PBR) have been implicated in growth control of various tumor models, but they have not been studied yet in esophageal cancer. We used esophageal cancer cell lines and primary cell cultures of human esophageal cancers and evaluated (i) expression and localization of PBR; (ii) PBR-ligand-induced inhibition of cell growth; (iii) induction of apoptosis; and (iv) alterations in cell cycle. Expression of PBR was detected both in cell lines and in primary cell cultures of human esophageal cancers. PBR was localized in the mitochondria. The PBR-specific ligands FGIN-1-27 and PK 11195, but not the centrally acting benzodiazepine clonazepam or the indolacetamide FGIN-1-52, neither of which displaying any affinity to the PBR, inhibited cell proliferation. FGIN-1-27 and PK 11195, but not clonazepam, potently induced apoptosis. FGIN-1-27 was shown to sequentially decrease the mitochondrial membrane potential, then to activate caspase-3 and finally to cause DNA fragmentation. In addition, PBR-specific ligands induced cell cycle arrest in the G1/G0 phase. Our data qualify PBR-specific ligands as innovative proapoptotic and antiproliferative substances. They might prove suitable for the treatment of esophageal cancer.