Enhancement of cisplatin sensitivity in lewis lung carcinoma by liposome-mediated delivery of a survivin mutant

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.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.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.There is a great deal of evidence that cisplatin (cis-diammine dichloroplatinum (II); CDDP) induces apoptosis in many tumor cell types. In the clinic, determining the greatest anti-tumoral efficiency using the lowest possible dose is a very difficult problem. Genetic therapy is considered to have enormous potential for resolving this issue.A novel member of the inhibitor of apoptosis protein family (IAP), designated survivin [1], was recently identified by hybridization screening of human genomic libraries with the complementary DNA (cDNA) of a factor Xa receptor, effector cell protease receptor 1[2]. Unlike all other IAPs, survivin is expressed during development and by common human cancers, but is undetectable or de