Intratumoral delivery of docetaxel enhances antitumor activity of Ad-p53 in murine head and neck cancer xenograft model.

PURPOSE: The aim of this study is to determine the ability of intratumorally delivered docetaxel to enhance the antitumor activity of adenovirus-mediated delivery of p53 (Ad-p53) in murine head and neck cancer xenograft model. MATERIALS AND METHODS: A xenograft head and neck squamous cell carcinoma mouse model was used. Mice were randomized into 4 groups of 6 mice receiving 6 weeks of biweekly intratumoral injection of (a) diluent, (b) Ad-p53 (1 x 10(10) viral particles per injection), (c) docetaxel (1 mg/kg per injection), and (d) combination of Ad-p53 (1 x 10(10) viral particles per injection) and docetaxel (1 mg/kg per injection). Tumor size, weight, toxicity, and overall and disease-free survival rates were determined. RESULTS: Intratumoral treatments with either docetaxel alone or Ad-p53 alone resulted in statistically significant antitumor activity and improved survival compared with control group. Furthermore, combined delivery of Ad-p53 and docetaxel resulted in a statistically significant reduction in tumor weight when compared to treatment with either Ad-p53 or docetaxel alone. CONCLUSION: Intratumoral delivery of docetaxel enhanced the antitumor effect of Ad-p53 in murine head and neck cancer xenograft model. The result of this preclinical in vivo study is promising and supports further clinical testing to evaluate efficacy of combined intratumoral docetaxel and Ad-p53 in treatment of head and neck cancer.

BMS-275183-induced gene expression patterns in head and neck carcinoma.

PURPOSE: BMS-275183 is an orally bioavailable taxane that has antitumor activity in preclinical cancer models. However, limited BMS-275183 studies have been performed in head and neck squamous cell carcinoma (HNSCC) cell lines. The purpose of this study is to identify the biological activity of BMS-275183 on HNSCC. MATERIALS AND METHODS: Head and neck squamous cell carcinoma cell lines, HN6, HN12, and HN30, were exposed to BMS-275183. BMS-275183-induced growth suppression, cell-cycle arrest, and apoptosis were measured. Then, expression of selected proteins that were induced by BMS-275183 was determined by Western blot analysis. RESULTS: BMS-275183 suppressed proliferation and induced G(2)M arrest and apoptosis in all HNSCC cell lines tested. BMS-275183 altered the expression of cell-cycle regulators, such as cyclin A and cyclin B1. The expression of E2F and p27 was decreased and increased, respectively, in all HNSCC cell lines. Cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) were increased in HN6 and HN12 cells. epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) expression were decreased by BMS-275183 in HN6 and HN30 cell lines, whereas phosphorylated epidermal growth factor receptor (pEGFR) was decreased in only HN6 cells. CONCLUSIONS: BMS-275183 induced cellular apoptosis, cell-cycle arrest, and altered gene expression in HNSCC via molecular pathways similar to other taxanes. These preclinical experiments suggest that BMS-275183 may be useful in treating HNSCC and that the aforementioned genes can potentially be used as surrogate end-point biomarkers.

Presence and density of Helicobacter pylori biofilms in human gastric mucosa in patients with peptic ulcer disease.

Our purpose was to use endoscopically directed biopsies and scanning electron microscopy to quantify Helicobacter pylori biofilm density on the surface of human gastric mucosa in urease-positive and -negative patients. Participating patients underwent flexible esophago-gastro-duodenoscopies coupled with gastric mucosal biopsies. Rapid urease testing was performed on all specimens to determine the presence of H. pylori, followed by scanning electron microscopy to identify the existence of biofilms. Samples were then analyzed using Carnoy Image Analysis Software to determine percent biofilm coverage of the total surface area. These data were compared to control specimens that were urease negative. Of the patients who tested urease positive for H. pylori, the average percent of total surface area covered by biofilms was 97.3%. Those testing negative had an average surface area coverage of only 1.64%. These differences were determined to be statistically significant at the 0.0001 level. This study demonstrates that compared with controls, urease-positive specimens have significant biofilm formation, whereas urease-negative specimens have little to none. This was reflected in the significantly increased biofilm surface density in urease positive specimens compared with urease-negative controls.

Identification of Helicobacter pylori biofilms in human gastric mucosa.

The purpose of this study was to use endoscopically directed biopsies and scanning electron microscopy (SEM) to document the existence of Helicobacter pylori biofilms in human gastric mucosa. Patients underwent flexible esophagogastroduodenoscopies with three gastric mucosal biopsies. Rapid urease testing was performed to determine the presence or absence of H pylori. Urease-positive and urease-negative control specimens were imaged with SEM to obtain detailed images of gastric mucosa for the identification of biofilm colonies. Samples were obtained from patients who underwent esophagogastroduodenoscopies. Eleven were found to be H pylori positive and nine were H pylori negative. These were imaged at 500x and 1000x with electron microscopy. Dense, mature biofilms were present and attached to the cell surface of H pylori-positive specimens and were absent in urease-negative controls. Photomicrographs were obtained. Biofilms are complex microbiological ecosystems where sessile bacteria surround themselves in a protective matrix. This lifestyle affords protection, allows for growth in hostile environments, and alters host physiology. Many have hypothesized that H pylori infections resulting in gastric ulcers may be a manifestation of biofilms. Our investigation is the first to photographically document the existence of H pylori biofilms on human gastric mucosa. This elucidation of the ecology and pathophysiology of the mucosa of the organism is important to our understanding of a potential mechanism of this organism's resistance to current therapy and how to better eradicate it in the future.