Adenovirus-mediated gene therapy for human head and neck squamous cell cancer in a nude mouse model.
Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene followed by ganciclovir administration was used to treat human head and neck cancer in nude mice. Tumors were generated by transcutaneous needle injection of 6 x 10(6) human squamous carcinoma cells into the floor of the mouth. After 14 days, 10(10) particles of a replication-defective recombinant adenovirus containing the herpes simplex virus thymidine kinase gene (ADV/RSV-tk) were injected directly into the tumors. The mice subsequently received ganciclovir injections for six consecutive days and were sacrificed at 21 days post tumor cell implantation. Clinical response to the treatment was assessed by computer-imaged morphometric analysis of cross sectional area of nonnecrotic tumor and mitotic activity, which were used for the calculation of a tumor index. The median tumor index value of the treatment group was 280- to 2400-fold smaller than controls which did not receive the therapeutic gene (P < 0.001-0.016), and three-quarters of the treatment group had tumor index values that were indicative of near total tumor regression. Survival studies show that 50% of the ADV/RSV-tk-treated mice are free of tumor at 160 days post adenovirus injection, while all controls died or required sacrifice within 43 days. These results demonstrate that clinically effective in vivo treatment of human squamous cell cancer can be achieved using adenovirus-mediated gene therapy.
O'Malley
B W
BW
Howard Hughes Medical Institute, Department of Otorhinolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas 77030.
Chen
S H
SH
Schwartz
M R
MR
Woo
S L
SL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001358:Avian Sarcoma Viruses / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000628:therapy*; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics
D014764:Viral Proteins; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir