An in vivo evaluation of docetaxel delivered intratumorally in head and neck squamous cell carcinoma.
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.
Yoo
George H
GH
Department of Otolaryngology-Head and Neck Surgery, Division of Hematology/Oncology, Wayne State University, Detroit, MI 48201, USA.
Subramanian
Geetha
G
Boinpally
Ramesh R
RR
Iskander
Andrew
A
Shehadeh
Nasfat
N
Oliver
Jeffrey
J
Ezzat
Waleed
W
Piechocki
Marie P
MP
Ensley
John F
JF
Lin
Ho-Sheng
HS
Shibuya
Terry Y
TY
Polin
Lisa
L
Parchment
Ralph E
RE
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel