Antitumor effect of mSurvivinThr34→Ala in murine colon carcinoma when administered intravenously.
Colorectal cancer is one of the most common cancers. Survivin is strongly immunogenic in a fraction of colorectal cancer patients. The present study was designed to determine whether full-length mouse Survivin dominant-negative mutant SurvivinT34A has the antitumor activity in a murine colon carcinoma model. The complex of cationic liposome (DOTAP/Chol) to plasmid pORF9-mSurvivin T34A was administered intravenously in a mouse subcutaneous (S. C.) CT 26 tumor model. Apoptotic cells and anti-angiogenesis were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31, respectively. A 4 h 51Cr release assay was performed to determine Survivin-specific cytotoxicity. The adoptive transfer of CD8+ or CD4+ T-lymphocytes assay was to further explore the roles of immune cell subsets. We demonstrated the complex of cationic liposome (DOTAP/Chol) to plasmid pORF9--mSurvivin T34A when administered intravenously induced an efficient antitumor activity in a S. C. CT26 tumor model in mice. The main mechanism is involved in three aspects: triggering the apoptosis of tumor cells, inhibiting angiogenesis, and inducing Survivin-specific immune response. Our observations may have potential implications for the further exploration of the treatment of human colorectal cancer by intravenous delivery of dominant-negative mutant Survivin T34A.
Li
Hong-xia
HX
Department of Gynecology and Obstetrics, Second West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
Zhao
Xin-yu
XY
Wang
Lian
L
Wang
Yong-sheng
YS
Kan
Bin
B
Xu
Jian-rong
JR
Li
Jiong
J
Wen
Yan-Jun
YJ
Peng
Xing-chen
XC
Chen
Xiang
X
Yan
Fei
F
Ye
Bin
B
Du
Xiao-bo
XB
Zhao
Ju-mei
JM
Yi
Tao
T
Chen
Xian-cheng
XC
Du
Xiao-xia
XX
Wei
Yu-quan
YQ
Zhao
Xia
X
D019264:Adoptive Transfer; D000409:Alanine / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000077022:Survivin; D013912:Threonine / Q000235:genetics
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D012097:Repressor Proteins; D000077022:Survivin; D013912:Threonine; D000409:Alanine