Enhancement of Ad-p53 therapy with docetaxel in head and neck cancer.
OBJECTIVE
The objective of this project was to determine the mechanisms in which docetaxel enhances Ad-p53 tumor suppressive effects in head and neck cancer.


BACKGROUND
In advanced head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate is less than 40%. Because patients with advanced HNSCC have a high rate of local-regional failure (40-60%) with existing treatment modalities, aggressive local therapy approaches need to be developed. Previous data show that docetaxel or Ad-p53 alone have significant anti-tumor activity in HNSCC. Before testing whether a combination approach (Ad-p53 and docetaxel) could be developed in clinical trials, preclinical experiments were performed.


METHODS
The p53 gene was overexpressed in 2 head and neck squamous carcinoma (HNSCC) cell lines, HN30 and HN12, and a murine Balb/c mucoepidermoid carcinoma (BMEC) cell line. Docetaxel's enhancement of adenoviral transduction (bGAL expression), coxsakie-adenovirus receptor (CAR) expression, and Ad-p53 induction of apoptosis (Annexin V expression) were measured. The modulation of regulators in the cell cycle, apoptosis and signal transduction pathways were measured using Western blot.


RESULTS
Docetaxel increased adenoviral transduction, which was dependent on the dose of docetaxel and levels of Ad-bGAL. The enhanced viral transduction was due in part to the upregulation of the CAR protein. Pretreatment with docetaxel enhanced Ad-p53-induced apoptosis through increased expression of exogenous p53. Together, the combination of docetaxel and Ad-p53 altered expression of key regulators in the cell cycle, apoptosis and signal transduction pathways with an increase in the expression of p53, bax, cleaved PARP, cleaved caspase-3 and phosphorylation of c-Jun at position at Ser. Cyclin A and B1 expression were down regulated by docetaxel and Ad-p53. When comparing the docetaxel-resistant to sensitive cell lines, the altered expression of p27 and skp1 by docetaxel and Ad-p53 were dissimilar between these cell lines.


CONCLUSIONS
Docetaxel enhanced Ad-p53 transduction and increased expression of exogenous p53 gene transfer, apoptosis, and antitumor mechanisms. These results support a clinical combination of docetaxel with p53 gene therapy in patients with head and neck cancer.
Yoo
George H
GH
Department of Otolaryngology-Head and Neck Surgery, Wayne State University, Detroit, Michigan 48201, USA.
Piechocki
Marie P
MP
Oliver
Jeffery
J
Lonardo
Fulvio
F
Zumstein
Lou
L
Lin
Ho-Sheng
HS
Kim
Harold
H
Shibuya
Terry Y
TY
Shehadeh
Nasfat
N
Ensley
John F
JF
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004770:Enterovirus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D014176:Protein Biosynthesis / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; C080625:taxane