Head and neck squamous cell carcinoma targeted chemosensitization.
OBJECTIVE
The current treatment for advanced head and neck squamous cell carcinoma continues to result in poor outcomes. The purpose of this study is to investigate the benefit of fibroblast growth factor 2-targeted adenovirus-mediated mutant-Rad50 (FGF2-Ad-Rad50) gene transfer in enhancing chemosensitization for head and neck squamous cell carcinoma and reducing chemotoxicity.


METHODS
Randomized controlled laboratory study.


METHODS
University of Pennsylvania, Philadelphia, PA.


METHODS
Human head and neck squamous cell carcinoma tumor cells and a mouse model with human head and neck squamous cell carcinoma were used for this study. There were five mice in each study group. FGF2-fab' molecule was conjugated with an adenoviral mutant-Rad50 construct. FGF2-targeted transgene expression efficiency was evaluated in vitro. Tumor cytotoxicity and growth inhibition were examined after combined FGF2-Ad-Rad50 with cisplatin treatment in vitro and in vivo. Anti-tumor mechanisms were investigated.


RESULTS
FGF2-targeted gene transfer approach significantly improved transgene expression in head and neck squamous cell carcinoma tumor cells over a nontargeted approach (207.51+/-33.62 vs 51.44+/-8.28, respectively). FGF2-Ad-Rad50 with cisplatin demonstrated a superior tumor suppression effect (264.5+/-124.1 mm3 vs 567.1+/-267.6 mm3), increased DNA double-strand breaks (1349+/-51.67 vs 774+/-28.56), and anti-angiogenesis (%ROI: 0.76%+/-0.38% vs 2.10%+/-1.66%) in tumor cells over nontargeted adenovirus.


CONCLUSIONS
Combination of FGF2-Ad-Rad50 with cisplatin significantly improves anti-tumor effect by targeting DNA repair systems and tumor angiogenesis. The great benefit of this strategy supports clinical trial for novel treatment of head and neck squamous cell carcinoma.
Figures
Mindy R
MR
Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Wobb
Jessie
J
Araki
Koji
K
Liu
Tingyan
T
Xu
Lei
L
Zhu
Hanjing
H
O'Malley
Bert W
BW
Li
Daqing
D
D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011897:Random Allocation; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016222:Fibroblast Growth Factor 2; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes; D002945:Cisplatin