A safe, effective in vivo gene therapy for melanoma using tyrosinase promoter-driven cytosine deaminase gene.
This study was designed to develop a safe, effective gene therapy for disseminated melanoma. We constructed retroviral vectors containing a tyrosinase promoter-cytosine deaminase expression cassette (Tyr/CD), and demonstrated that the tyrosinase promoter conferred a selective expression of cytosine deaminase (CD) gene in B16 melanoma cells, especially when the Tyr/CD cassette inserted in 3'LTR region of a retroviral vector. In vivo gene therapy for the intraperitoneally disseminated melanoma using Tyr/CD retrovirus-producing cells and 5-fluorocytosine (5-FC) showed that retroviruses produced in situ were capable of infecting tumor xenografts and bone marrow cells in animal model, and survival rates were prolonged significantly as compared with those treated with CD2 retrovirus-producing cells and 5-FC. Importantly, the treatment-related bone marrow suppression was not observed in the former treatment, while profound bone marrow suppression was observed in the latter treatment. In vivo gene therapy using retrovirus-producing cells containing suicide gene under the control of a tissue-specific promoter and 5-FC administration is safer and more effective for the treatment of disseminated melanoma, as compared with retrovirus-producing cells containing the gene under the control of a universal promoter and 5-FC.
Cao
G
G
Department of Microbiology, Second Military Medical University, Shanghai, China. guangwen@ecmu.org.cn
Zhang
X
X
He
X
X
Chen
Q
Q
Qi
Z
Z
D000818:Animals; D001854:Bone Marrow Cells; D016923:Cell Death; D043525:Cytosine Deaminase; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008546:Melanoma, Experimental / Q000201:enzymology / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D014442:Monophenol Monooxygenase / Q000235:genetics*; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012190:Retroviridae / Q000235:genetics; D015996:Survival Rate; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D014442:Monophenol Monooxygenase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase