Enhancement of cisplatin sensitivity in Lewis Lung carcinoma by liposome-mediated delivery of a survivin mutant.
BACKGROUND
A high concentration of cisplatin (CDDP) induces apoptosis in many tumor cell lines. CDDP has been administered by infusion to avoid severe toxicity. Recently, it has been reported that changes in survivin expression or function may lead to tumor sensitization to chemical and physical agents. The aim of this study was to determine whether a dominant-negative mouse survivin mutant could enhance the anti-tumor activity of CDDP.


METHODS
A plasmid encoding the phosphorylation-defective dominant-negative mouse survivin threonine 34-->alanine mutant (survivin T34A) complexed to a DOTAP-chol liposome (Lip-mS) was administered with or without CDDP in Lewis Lung Carcinoma (LLC) cells and in mice bearing LLC tumors, and the effects on apoptosis, tumor growth and angiogenesis were assessed. Data were analyzed using one-way analysis of variance(ANOVA), and a value of P < 0.05 was considered to be statistically significant.


RESULTS
LLC cells treated with a combination of Lip-mS and CDDP displayed increased apoptosis compared with those treated with Lip-mS or CDDP alone. In mice bearing LLC tumors and treated with intravenous injections of Lip-mS and/or CDDP, combination treatment significantly reduced the mean tumor volume compared with either treatment alone. Moreover, the antitumor effect of Lip-mS combined with CDDP was greater than their anticipated additive effects.


CONCLUSIONS
These data suggest that the dominant-negative survivin mutant, survivin T34A, sensitized LLC cells to chemotherapy of CDDP. The synergistic antitumor activity of the combination treatment may in part result from an increase in the apoptosis of tumor cells, inhibition of tumor angiogenesis and induction of a tumor-protective immune response.
Yu
Dan-Dan
DD
West China Hospital, Sichuan University, Chengdu, China.
Wang
Chun-Ting
CT
Shi
Hua-Shan
HS
Li
Zhi-Yong
ZY
Pan
Li
L
Yuan
Qing-Zhong
QZ
Leng
Fei
F
Wen
Yuan
Y
Chen
Xiang
X
Wei
Yu-Quan
YQ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009154:Mutation; D009389:Neovascularization, Pathologic; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D002945:Cisplatin
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