Therapeutic effects of survivin dominant negative mutant in a mouse model of prostate cancer.
OBJECTIVE
Patients with localized prostate cancer can usually achieve initial response to conventional treatment. However, most of them will inevitably progress to advanced disease stage. There is a clear need to develop innovative and effective therapeutics for prostate cancer. Mouse survivin T34A (mS-T34A) is a phosphorylation-defective Thr34 → Ala dominant negative mutant, which represents a potential promising target for cancer gene therapy. This study was designed to determine whether mS-T34A plasmid encapsuled by DOTAP-chol liposome (Lip-mS) has the anti-tumor activity against prostate cancer, if so, to further investigate the possible mechanisms.


METHODS
In vitro, TRAMP-C1 cells were transfected with Lip-mS and examined for apoptosis by PI staining and flow cytometric analysis. In vivo, subcutaneous prostate cancer models were established in C57BL/6 mice, which were randomly assigned into three groups to receive i.v. administrations of Lip-mS, pVITRO2-null plasmid complexed with DOTAP-chol liposome (Lip-null) or normal saline every 2 days for eight doses. Tumor volume was measured. Tumor tissues were inspected for apoptosis by TUNEL assay. Microvessel density (MVD) was determined by CD31 immunohistochemistry. Alginate-encapsulated tumor cell test was conducted to evaluate the treatment effect on angiogenesis.


RESULTS
Administration of Lip-mS resulted in significant inhibition in the growth of mouse TRAMP-C1 tumors. The anti-tumor response was associated with increased tumor cell apoptosis and decreased microvessel density.


CONCLUSIONS
The present study may be of importance in the exploration of the potential application of Lip-mS in the treatment of a broad spectrum of tumors.
Pan
Li
L
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Chengdu, Sichuan, People's Republic of China.
Peng
Xing-Chen
XC
Leng
Fei
F
Yuan
Qing-Zhong
QZ
Shan
Yan
Y
Yu
Dan-Dan
DD
Li
Zhi-Yong
ZY
Chen
Xiang
X
Xiao
Wen-Jing
WJ
Wen
Yuan
Y
Ma
Tian-Tai
TT
Yang
Li
L
Mao
Yong-Qiu
YQ
Yang
Han-Shuo
HS
Wei
Yu-Quan
YQ
Wang
Chun-Ting
CT
D000818:Animals; D045744:Cell Line, Tumor; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D015316:Genetic Therapy; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000627:therapeutic use; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D012097:Repressor Proteins / Q000235:genetics* / Q000627:therapeutic use; D000077022:Survivin
C117749:Birc5 protein, mouse; D005229:Fatty Acids, Monounsaturated; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D012097:Repressor Proteins; D000077022:Survivin; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane