Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 Jiangsu, PR China.
Int J Oncol. 2010 Oct;37(4):935-41. doi: 10.3892/ijo_00000744.
Gene transfer of CD40 ligand (CD40L) holds promise as a novel therapy for lymphoid malignancies and a number of solid carcinomas because of its multiple anti-tumor activities. However, membrane-bound CD40L can be cleaved into a soluble form, sCD40L, which contributes to systemic inflammatory and cardiovascular diseases, and induces survival signals in the absence of protein synthesis block, suggesting a deleterious side effect of CD40L gene therapy. We generated a plasmid encoding non-cleavable human CD40L mutant (pcDNA3.1+-CD40L-M) to determine the direct anti-proliferative and pro-apoptotic effects in CD40-positive lung adenocarcinoma cell line A549, to verify activation of immature dentritic cells (DCs) by co-cultivation with the transfected A549 cells and to evaluate the lower expression of sCD40L relative to that of wild-type CD40L (CD40L-WT) transfectant in cell-free supernatants. These studies suggest that gene transfer of the membrane-stable CD40L mutant into CD40-positive cells may provide an efficient and safe method to treat non-small cell lung cancer.
CD40 配体（CD40L）的基因转移因其多种抗肿瘤活性而有望成为治疗淋巴恶性肿瘤和多种实体癌的新疗法。然而，膜结合的 CD40L 可被切割成可溶性形式 sCD40L，这会导致全身炎症和心血管疾病，并在没有蛋白质合成阻断的情况下诱导存活信号，表明 CD40L 基因治疗存在有害的副作用。我们生成了一种编码不可切割的人 CD40L 突变体的质粒（pcDNA3.1+-CD40L-M），以确定其在 CD40 阳性肺腺癌细胞系 A549 中的直接抗增殖和促凋亡作用，通过与转染的 A549 细胞共培养来验证未成熟树突状细胞（DC）的激活，并评估细胞游离上清液中 sCD40L 的表达相对于野生型 CD40L（CD40L-WT）转染体的降低。这些研究表明，将膜稳定的 CD40L 突变体基因转移到 CD40 阳性细胞中可能为治疗非小细胞肺癌提供一种有效且安全的方法。
