Therapy of head and neck squamous cell carcinoma with replicative adenovirus expressing tissue inhibitor of metalloproteinase-2 and chemoradiation.
Recent studies have demonstrated the efficacy of targeted therapy combined with radiotherapy in head and neck squamous cell carcinoma (HNSCC). We hypothesized that a combination treatment including a replicating adenovirus armed with tissue inhibitor of metalloproteinase-2 (TIMP-2), radiation and Cisplatin will augment treatment response and reduce tumor growth in vivo of HNSCC xenografts. Both single-agent (TIMP-2 virus, radiation and Cisplatin) and the combination therapies were evaluated in vitro and in vivo. The efficacy of both single-agent and combination therapies in vivo was determined by monitoring tumor growth and immunohistochemistry. Treatment with replicative Ad-TIMP-2 virus and radiation decreased cell viability in vitro and resulted in an additional antiangiogenic response in vivo. Tumor response rates to treatment with replicative Ad-TIMP-2, radiation, Cisplatin or combination therapies ranged from limited inhibition of tumor growth of the single-agent therapy to a statistically significant additive antitumor response with the combination therapies. Replicative Ad-TIMP-2+radiation+Cisplatin in the SCC1 nude mice demonstrated the greatest response rates in tumor growth and angiogenesis. Combination of Ad-TIMP-2 gene therapy with radiation and the triple treatment group resulted in an augmented therapeutic response. This is the first report of the potential benefits of combining radiation and MMP inhibitor treatment.
McNally
L R
LR
Division of Radiation Biology, Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35294-6832, USA.
Rosenthal
E L
EL
Zhang
W
W
Buchsbaum
D J
DJ
D000260:Adenoviruses, Human / Q000235:genetics* / Q000502:physiology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor / Q000637:transplantation / Q000821:virology; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy; D050130:Oncolytic Virotherapy; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D011993:Recombinant Fusion Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D002945:Cisplatin