Posts tagged: Timothy Stevens

Timothy Stevens, ’10

Yoo, G. H., Kafri, Z., Ensley, J. F., Lonardo, F., Kim, H., Folbe, A. J., Won, J., Stevens, T., Lin, H. (2010). Xrp6258-Induced Gene Expression Patterns in Head and Neck Cancer Carcinoma. The Laryngoscope. Published online April 20, 2010.

Abstract: XRP6258 is a novel taxoid, which has antitumor activity in preclinical mouse orthotopic and human xenograft cancer models. However, limited XRP6258 studies have been performed in head and neck squamous cell carcinoma cells (HNSCC). The objective of this study is to identify the antitumor activity of XRP6258 in HNSCC cell line models.HNSCC cells (HN30 and HN12) were exposed to either XRP6258 or docetaxel. XRP6258-induced growth suppression, cell cycle arrest and apoptosis were measured. Further, XRP6258-induced expression patterns of selected genes were compared to docetaxel-induced expression patterns using Western blot analysis.XRP6258 suppressed proliferation and induced G2M arrest and apoptosis in both of the cell lines tested. XRP6258 and docetaxel produced similar alteration in the expression of cell cycle regulators, such as cyclin A and cyclin B1. The expression of E2F and EGFR were decreased in both XRP6258 and docetaxel-treated HNSCC cells. Finally, XRP6258 induced a greater level of bcl2 phosphorylation than docetaxel in HN12 cell line.XRP6258 appeared to have a similar mechanism of action as docetaxel in the two HNSCC cell lines studied. XRP6258 induced cell cycle arrest, growth suppression, and apoptosis by altering gene expression patterns similar to that induced by docetaxel. These preclinical experiments suggest that XRP6258 may be useful in treating HNSCC, and the aforementioned genes can potentially be used as surrogate endpoint biomarkers. Laryngoscope, 2010

Timothy Stevens, ’10

Yoo, G. H., Subramanian, G., Ezzat, W. H., Stevens, T., Tulunay, O. E., Tran, V. R., et al. (2010). Intratumoral Delivery of Docetaxel Enhances Antitumor Activity of Ad-P53 in Murine Head and Neck Cancer Xenograft Model. American Journal of Otolaryngology, 31(2), 78-83.

Abstract: 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. 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 × 1010 viral particles per injection), (c) docetaxel (1 mg/kg per injection), and (d) combination of Ad-p53 (1 × 1010 viral particles per injection) and docetaxel (1 mg/kg per injection). Tumor size, weight, toxicity, and overall and disease-free survival rates were determined. 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. 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.

Timothy Stevens, ’10

Yoo, G. H., Subramanian, G., Stevens, T., Piechocki, M. P., Ensley, J. F., Kucuk, O., et al. (2008). Effect of Docetaxel on the Surgical Tumor Microenvironment of Head and Neck Cancer in Murine Models. Archives of Otolaryngology – Head & Neck Surgery, 134(7), 735-742.

Abstract: OBJECTIVES: To identify the antitumor activity and wound-healing effect of docetaxel delivered in the surgical tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). DESIGN: Control and experimental series. SETTING: Academic medical center. SUBJECTS: BALB/c and severe combined immunodeficiency mice. INTERVENTION: Intrawound (IW) docetaxel therapy was tested in 3 HNSCC xenograft and 2 taxane-resistant models. Intratumoral (IT) docetaxel therapy was further tested in the 2 taxane-resistant models. MAIN OUTCOME MEASURES: Tumor size, survival, and wound toxic effects were measured. The effect of docetaxel on various factors involved in wound healing and tumor growth within the surgical tumor microenvironment was also analyzed. RESULTS: In a pilot study using BALB/c mice, IW docetaxel therapy was not associated with problems in wound healing. Using the HN6, HN12, and HN30 HNSCC xenograft model, IW docetaxel prevented tumor growth and improved survival when compared with controls. No local or systemic toxic effect or wound-healing problem was noted. Using taxane-resistant xenograft lung cancer (H460/T800) and syngeneic salivary cancer (BALB/c mucoepidermoid carcinoma) models, IW therapy did not delay tumor growth. An antitumor effect was detected with repeated docetaxel injections in the H460/T800 taxane-resistant model but not in the BALB/c mucoepidermoid carcinoma model. Docetaxel inhibited the expression of growth factors and receptors in tumor cells; however, it did not inhibit the level of wound-healing growth factors in the surgical tumor microenvironment. CONCLUSIONS: These preclinical results support further testing of IW docetaxel treatment in HNSCC. Docetaxel appears to exert antitumor activity without affecting factors involved in wound healing in the tumor microenvironment.

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