 |
|
An In Vivo Evaluation of Docetaxel Delivered Intratumorally in Head and Neck Squamous Cell Carcinoma
George H. Yoo, MD;
Geetha Subramanian, MD;
Ramesh R. Boinpally, PhD;
Andrew Iskander, MD;
Nasfat Shehadeh, MD;
Jeffrey Oliver, BS;
Waleed Ezzat, BS;
Marie P. Piechocki, PhD;
John F. Ensley, MD;
Ho-Sheng Lin, MD;
Terry Y. Shibuya, MD;
Lisa Polin, PhD;
Ralph E. Parchment, PhD
Arch Otolaryngol Head Neck Surg. 2005;131:418-429.
Objective To identify activity and biological mechanisms of intratumoral (IT) docetaxel on head and neck squamous cell carcinoma (HNSCC).
Methods Docetaxel IT therapy was tested in xenograft models of 2 HNSCC lines, HN30 and HN12. The overall and disease-free survival rates, tumor growth, and toxic effects were measured. The pharmacokinetic profiles of docetaxel in plasma and tumor were compared after IT and intravenous (IV) administration. Comparisons between common and supradoses of docetaxel with regard to expression of regulators in the cell cycle, apoptosis, and signal transduction pathways were determined using Western blot analysis.
Results In the HN30 and HN12 xenograft models, IT docetaxel improved overall as well as disease-free survival and reversed tumor growth. The only toxic effects noted were local (alopecia and skin breakdown). Skin breakdown resolved in all cases. At equivalent dosing levels, IT docetaxel achieved a 26-fold higher peak tumor concentration and 24-fold longer tumor exposure than IV treatment. Furthermore, limited plasma exposure was noted with IT docetaxel. Supradose levels of docetaxel produced distinct protein expression patterns for regulators of the cell cycle (cyclins A and B, p21, and p27), apoptosis (cleaved caspase-3 and cleaved PARP), and signal transduction (EGFR, pEGFR, pc-Jun, and pERK) in HNSCC, which supports a distinctive mechanism of action for supradose docetaxel levels. Since levels of cleaved caspase-3 and PARP, markers of apoptosis, were only elevated with lower doses, the observed cell death at supradose levels was probably due to necrosis.
Conclusions Injections of IT docetaxel at usual and supradoses are associated with a pharmacokinetic profile and biological mechanism distinct from those observed with usual IV doses. It is calculated that IT therapy in men will increase peak concentrations of docetaxel in tumors by 1000-fold over the conventional IV dose used clinically. These preclinical results support further testing of IT docetaxel in HNSCC.
Author Affiliations: Departments of Otolaryngology–Head and Neck Surgery (Drs Yoo, Subramanian, Iskander, Piechocki, Ensley, and Lin and Messrs Oliver and Ezzat) and Medicine, Division of Hematology/Oncology (Drs Boinpally, Shehadeh, Ensley, Polin, and Parchment), Wayne State University and Barbara Ann Karmanos Cancer Institute, Detroit, Mich; and Department of Otolaryngology–Head & Neck Surgery (Dr Shibuya), University of California Irvine College of Medicine, Irvine.
|
