Growth Inhibition of Human Multiple Myeloma Cells by an Oncolytic Adenovirus Carrying the CD40 Ligand Transgene
Growth Inhibition of Human Multiple Myeloma Cells by an Oncolytic Adenovirus Carrying the CD40 Ligand Transgene
复制标题
DOI：
10.1158/1078-0432.ccr-09-0451
复制
发表时间：
2009-08-01
影响因子：
11.5
通讯作者：
Tong, Alex W.
中科院分区：
文献类型：
--
作者：
Fernandes, Margret S.;Gomes, Erica M.;Tong, Alex W.
目的：重组CD 40配体（CD 40 L）在人多发性骨髓瘤（MM）中的生长抑制活性已得到充分证实。我们研究了条件复制型溶瘤腺病毒AdEHCD 40 L对MM靶向的CD 40 L的表达。实验设计：在体外和体内测定AdEHCD 40 L的生长调节活性。AdEHCD 40 L和亲本病毒（AdEHCD 4）感染的文化差异分析允许识别的CD 40 L转基因调控的细胞和分子途径。结果：病毒E1 A和CD 40 L转基因的条件表达显示在人MM线RPMI 8226 [白细胞介素（IL）-6独立]和Kas-6/1（IL-6依赖）在缺氧条件下通常发现在MM原位。AdEHCD 40 L对MM细胞生长的抑制作用强于AdEHCD。这种增强的生长抑制活性通过与CD 40 L抗体共处理而被废除。化学抗性MM系（MR 20和LR 5）对AdEHCD 40 L处理类似地敏感。AdEHCD 40 L诱导细胞凋亡和S期细胞周期阻滞，同时独特地上调先前描述的促凋亡元件肿瘤坏死因子相关凋亡诱导配体Fas和IL-8。瘤内注射AdEHCD 40 L使严重联合免疫缺陷/hu RPMI 8226异种移植物的生长减少>50%，而AdEHCD使其减少28%。腺病毒六邻体和CD 40 L在AdEHCD 40 L治疗的肿瘤中检测到感染后第35天主要在坏死areas. Conclusions，提示病毒复制activity.Conclusions：这些研究结果表明，CD 40 L的行为与病毒溶瘤协同作用，通过激活细胞凋亡产生MM生长抑制。AdEHCD 40 L的直接生长抑制活性，以及CD 40 L的众所周知的免疫增强功能，可能在临床上适用于MM或浆细胞白血病的实验性治疗。
Purpose: The growth-inhibitory activity of recombinant CD40 ligand (CD40L) is well documented in human multiple myeloma (MM). We examined MM-targeted delivery of CD40L by a conditional replicative oncolytic adenovirus, AdEHCD40L.Experimental Design: The growth-regulatory activity of AdEHCD40L was determined in vitro and in vivo. Differential analysis with AdEHCD40L and parental virus (AdEHNull)-infected cultures allowed the identification of cellular and molecular pathways modulated by the CD40L transgene.Results: Conditional expression of viral E1A and CD40L transgene was shown in human MM lines RPMI 8226 [interleukin (IL)-6 independent] and Kas-6/1 (IL-6 dependent) under hypoxic conditions commonly found in MM in situ. AdEHCD40L inhibited MM cell growth more effectively than AdEHNull. This enhanced growth-inhibitory activity was abrogated by cotreatment with a CD40L antibody. Chemoresistant MM lines (MR20 and LR5) were similarly susceptible to AdEHCD40L treatment. AdEHCD40L induced apoptosis and S-phase cell cycle blockade while uniquely up-regulating the previously described proapoptotic elements tumor necrosis factor-related apoptosis-inducing ligand, Fas, and IL-8. Intratumoral injections of AdEHCD40L reduced the growth of severe combined immunodeficient/hu RPMI 8226 xenografts by >50% compared with 28% reduction by AdEHNull. Adenoviral hexon and CD40L were detected in AdEHCD40L-treated tumors at day 35 after infection primarily in necrotic areas, suggesting viral replicative activity.Conclusions: These findings show that CD40L acts in concert with viral oncolysis to produce MM growth inhibition through activation of cellular apoptosis. The direct growth-inhibitory activity of AdEHCD40L, together with the well-known immune-potentiating features of CD40L, may be clinically applicable for the experimental treatment of MM or plasma cell leukemia.