title: Enhancement of cisplatin sensitivity in Lewis Lung carcinoma by liposome-mediated delivery of a survivin mutant.
abstract: 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.
authors.affiliation: West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Yu
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Wang
authors.forename: Hua-Shan
authors.initials: HS
authors.lastname: Shi
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.forename: Qing-Zhong
authors.initials: QZ
authors.lastname: Yuan
authors.forename: Fei
authors.initials: F
authors.lastname: Leng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wen
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D002945:Cisplatin
references.citation: Oncogene. 2003 Jun 5;22(23):3539-47
references.pmid: 12789262
references.citation: Nature. 1998 Dec 10;396(6711):580-4
references.pmid: 9859993
references.citation: J Exp Clin Cancer Res. 2008 Sep 25;27:46
references.pmid: 18816410
references.citation: Ann Intern Med. 1984 May;100(5):704-13
references.pmid: 6370067
references.citation: J Clin Invest. 2002 Jan;109(2):285-6
references.pmid: 11805141
references.citation: Nat Cell Biol. 1999 Dec;1(8):461-6
references.pmid: 10587640
references.citation: Drug Resist Updat. 2002 Apr;5(2):65-72
references.pmid: 12135582
references.citation: Oncogene. 1998 Dec 24;17(25):3247-59
references.pmid: 9916987
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13103-7
references.pmid: 11069302
references.citation: Arch Otolaryngol Head Neck Surg. 2006 Jun;132(6):682-5
references.pmid: 16785416
references.citation: Am J Pathol. 1998 Jan;152(1):43-9
references.pmid: 9422522
references.citation: Lab Invest. 1999 Sep;79(9):1121-6
references.pmid: 10496530
references.citation: Br J Cancer. 2002 Mar 18;86(6):886-92
references.pmid: 11953819
references.citation: Cancer Res. 1998 Dec 1;58(23):5315-20
references.pmid: 9850056
references.citation: Eur J Cancer. 2002 Nov;38(17):2316-24
references.pmid: 12441269
references.citation: Cancer Res. 2000 Jun 1;60(11):2805-9
references.pmid: 10850418
references.citation: Exp Cell Res. 1999 Apr 10;248(1):30-43
references.pmid: 10094811
references.citation: Cancer Res. 1998 Nov 15;58(22):5071-4
references.pmid: 9823313
references.citation: FASEB J. 1995 Jul;9(10):860-5
references.pmid: 7615156
references.citation: Cancer Lett. 2000 Jan 1;148(1):65-71
references.pmid: 10680594
references.citation: J Surg Oncol. 1995 Dec;60(4):238-41
references.pmid: 8551732
references.citation: J Natl Cancer Inst. 2001 Oct 17;93(20):1541-52
references.pmid: 11604477
references.citation: Mol Cancer Ther. 2006 Jan;5(1):179-86
references.pmid: 16432177
references.citation: Clin Cancer Res. 2003 Dec 15;9(17):6523-33
references.pmid: 14695157
references.citation: J Cancer Res Clin Oncol. 1998 Jan;124(1):37-43
references.pmid: 9498833
references.citation: Nat Med. 1997 Aug;3(8):917-21
references.pmid: 9256286
references.citation: Cancer Res. 1994 Mar 15;54(6):1596-603
references.pmid: 8137265
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):635-40
references.pmid: 11149963
references.citation: Cancer Biol Ther. 2006 Apr;5(4):435-40
references.pmid: 16575205