Bortezomib sensitizes primary human esthesioneuroblastoma cells to TRAIL-induced apoptosis.

TNF-related apoptosis-inducing ligand (TRAIL), a promising novel anti-cancer cytokine of the TNF superfamily, and Bortezomib, the first-in-class clinically used proteasome inhibitor, alone or in combination have been shown to efficiently kill numerous tumor cell lines. However, data concerning primary human tumor cells are very rare. Using primary esthesioneuroblastoma cells we analyzed the anti-tumor potential and the mechanism employed by Bortezomib in combination with TRAIL for the treatment of this rare but aggressive tumor. Expression of components of the TRAIL pathway was analyzed in tumor specimens and isolated primary tumor cells at the protein level. Cells were treated with TRAIL, Bortezomib, and a combination thereof, and apoptosis induction was quantified. Clonogenicity assays were performed to elucidate the long-term effect of this treatment. Despite expressing all components of the TRAIL pathway, freshly isolated primary esthesioneuroblastoma cells were completely resistant to TRAIL-induced apoptosis. They could, however, be very efficiently sensitized by subtoxic doses of Bortezomib. The influence of Bortezomib on the TRAIL pathway was analyzed and showed upregulation of TRAIL death receptor expression, enhancement of the TRAIL death-inducing signaling complex (DISC), and downregulation of anti-apoptotic proteins of the TRAIL pathway. Of clinical relevance, TRAIL-resistant primary tumor cells could be repeatedly sensitized by Bortezomib, providing the basis for repeated clinical application schedules. This is the first report on the highly synergistic induction of apoptosis in primary esthesioneuroblastoma cells by Bortezomib and TRAIL. This combination, therefore, represents a promising novel therapeutic option for esthesioneuroblastoma.

Is PET superior to MRI in the pretherapeutic evaluation of head and neck squamous cell carcinoma?

OBJECTIVES: This study was designed to compare the effectiveness of positron emission tomography (PET) and magnetic resonance imaging (MRI) in the pretherapeutic staging of squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS: The study included 34 consecutive patients (27 males, 7 females; mean age 61 years; range 42 to 82 years) with SCC of the head and neck. All the patients underwent whole body [18F]fluorodeoxyglucose (FDG)-PET and MRI scans for pretherapeutic evaluation. Diagnoses were confirmed by histopathologic examination of endoscopic biopsy specimens. RESULTS: The sites of the primary tumors were the oropharynx (n=15, 44%), larynx (n=10, 29%), hypopharynx (n=8, 24%), and nasopharynx (n=1, 3%). Surgery was the treatment of choice in 20 patients (59%), including 23 neck dissections. Fourteen patients (41%) were treated with radiochemotherapy. Both PET and MRI were able to detect the primary tumor in 33 cases (97%). In two patients (6%), PET was able to detect distant metastases in the lung and iliac bone, all of which were confirmed by biopsies. Seven neck specimens (30%) showed lymph node metastasis. Sensitivity and specificity rates for detection of lymph node metastasis were 100% and 87.5% for PET, and 85.7% and 87.5% for MRI, respectively. CONCLUSION: Although PET seems to be superior to MRI in detecting nodal disease and distant metastases, it is still early to recommend it as a primary tool for pretherapeutic evaluation of head and neck cancers due to its limited availability and higher cost.