Combination gene therapy with p53 and Thoc1/p84 is more effective than either single agent in an animal model of human pancreatic adenocarcinoma.
Gene therapy utilizing tumor suppressor gene p53 has been tested in a number of cancers in both preclinical models and clinical trials. Despite the ability of p53 to significantly inhibit tumor growth in preclinical models, it has met with more limited clinical success. This is due, in part, to the observation that a substantial fraction of tumors are resistant to the effects of p53 expression. We have tested whether combination therapy with Thoc1/p84 and p53 is more effective than single gene therapy in a p53-resistant tumor model of human pancreatic adenocarcinoma. Infection with Thoc1/p84 and p53 adenovirus inhibits pancreatic cancer cell growth in vitro and in vivo to a greater extent than treatment with either one alone at the same total viral dose. Similar results are observed with Thoc1/p84 and Rb1 gene therapy. The data support the use of therapy that targets both the p53 and Thoc1/p84 pathways in tumors that are resistant to perturbation of the p53 pathway alone.
Yin
Shenmin
S
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Goodrich
David W
DW
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016601:RNA-Binding Proteins; D014162:Transfection; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C400546:THOC1 protein, human; D016159:Tumor Suppressor Protein p53