Inhibition of head and neck squamous cell carcinoma growth and invasion by the calcium influx inhibitor carboxyamido-triazole.

Local invasion and lymph node metastasis are correlated with a decreased overall survival in head and neck cancer patients and warrant new strategies to intervene in the metastatic cascade. One approach is to focus on the intracellular signaling pathways underlying the metastatic process. A common regulatory point in several signal transduction pathways is intracellular calcium homeostasis. We assessed the effect of a novel calcium influx inhibitor, carboxyamido-triazole (CAI), on the growth and invasive phenotype of cell lines derived from head and neck squamous cell carcinoma (HNSCC). CAI inhibited the growth of FaDu and EVSCC17M cells in a dose-dependent (IC50, 13-15 microM) and reversible manner. CAI also caused a generalized attenuation of receptor-mediated calcium elevation to several calcium mobilization agonists, including epidermal growth factor and bradykinin. The effects of CAI on the invasive phenotype of HNSCC cell lines were assessed by a chemo-invasion assay. HNSCC cell lines exhibited a range of invasive potential as measured by the capacity of tumor cells to penetrate a reconstituted basement membrane of Matrigel. HNSCCs were classified as highly invasive (EVSCC14M and EVSCC17M) or weakly invasive (EVSCC18, EVSCC19M, UMSCC10A, and FaDu). Treatment of HNSCC cell lines with 10 microM CAI for 24 h reduced invasion 2-14-fold in a dose-dependent manner. HNSCCs also exhibited different motilities as measured by a chemotaxis assay. EVSCC14M and EVSCC17M were highly motile, whereas EVSCC18, EVSCC19M, UMSCC10A, and FaDu were less motile. CAI reduced the migration of all cell lines. Conditioned medium from HNSCC cell lines was analyzed by zymography for production of Mr 72,000 type IV collagenase [matrix metalloproteinase (MMP)-2)] and Mr 92,000 type IV collagenase (MMP-9). All HNSCC cell lines secreted MMP-2 and/or MMP-9 into conditioned medium. Treatment of cells with 10 microM CAI for 24 h resulted in a reduction of both MMP-2 and MMP-9 production. The results demonstrate that CAI blocks cellular proliferation, migration, chemoinvasion, and MMP production by HNSCC in vitro and identify calcium-dependent signaling as a new target for inhibition of the malignant phenotype of HNSCC.

Treatment and prognosis of primary malignant small bowel tumors.

Primary malignant tumors of the small bowel are a heterogeneous group of tumors and are uncommon compared to tumors in other locations of the gastrointestinal tract. These tumors have been traditionally associated with a poor prognosis. The charts of 53 patients with primary malignant small bowel tumors at major Eastern Virginia Medical School teaching hospitals were retrospectively reviewed. Patient characteristics and presenting symptoms and signs were nonspecific. No single radiographic or endoscopic procedure was performed on every patient, and the diagnosis was suspected preoperatively in only 50 per cent of the patients. Tumors were most common in the ileum, and the most common histologic types were adenocarcinoma (53 per cent) and carcinoid (32 per cent). In univariate analysis, factors determining survival included histologic type, location of tumor, and stage. There was also a trend toward worse survival in patients receiving chemotherapy or radiation therapy, possibly due to patient selection factors. In multivariate analysis, only histology and stage significantly influenced survival. The overall 10-year survival of the entire group was 44 per cent. Small bowel tumors have a variable prognosis. A high index of suspicion and more frequent use of enteroclysis may lead to earlier detection and improved survival.