A midkine promoter-based conditionally replicative adenovirus for treatment of pediatric solid tumors and bone marrow tumor purging.
A midkine promoter-based conditionally replicative adenovirus for treatment of pediatric solid tumors and bone marrow tumor purging.
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发表时间：
2001-11
期刊：
影响因子：
11.2
通讯作者：
Y. Adachi;P. Reynolds;Masato Yamamoto;Minghui Wang;Koichi Takayama;S. Matsubara;T. Muramatsu;D. Curiel
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文献类型：
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作者：
Y. Adachi;P. Reynolds;Masato Yamamoto;Minghui Wang;Koichi Takayama;S. Matsubara;T. Muramatsu;D. Curiel
晚期神经母细胞瘤(NB)或尤文肉瘤(ES)的治疗是儿科肿瘤学面临的主要挑战之一。这两种恶性肿瘤对传统疗法都难以治愈，预后极差。大剂量清髓放化疗联合自体骨髓或外周血干细胞挽救是治疗这些疾病最积极的治疗方法之一，但通常会受到移植物残留肿瘤细胞的破坏。因此，在这种方法中，清除移植物中的肿瘤细胞是防止移植后复发的关键。我们研究了一种新的方法，通过使用条件复制性腺病毒(Ad)来消除骨髓或外周血干细胞移植中的肿瘤细胞，而不会造成干细胞损伤。ES和NB对Ad感染敏感，晚期NBs高水平表达生长分化因子中期因子(MK)。我们在本研究中证实，ES细胞系(SK-ES-1和RD-ES)也对Ad感染敏感，并表达高水平的MK。相反，CD34+干细胞对Ad感染是不耐受的，并且几乎不表达MK。一种由MK启动子调控E1基因表达的条件复制型Ad在NB或ES中获得了良好的病毒复制水平，并诱导了显着的肿瘤细胞杀伤。另一方面，该病毒在1000倍感染剂量下，即使在感染3h后也没有对CD34+细胞造成损害。我们的结论是，将这种复制能力强的Ad应用于造血移植物可能是一种简单但有效的方法来实现肿瘤细胞的完全净化。
The treatment of advanced neuroblastoma (NB) or Ewing's sarcoma (ES) is one of the major challenges in pediatric oncology. Both malignancies are refractory to conventional therapies and have an extremely poor prognosis. High-dose myeloablative radiochemotherapy with autologous bone marrow or peripheral blood stem cell rescue is one of the most aggressive treatments attempted for these diseases but is often undermined by residual tumor cells contaminating the graft. Thus, in this approach, purging of tumor cells from the graft is key to the prevention of relapse after transplantation. We investigated a novel approach to eliminate tumor cells from the bone marrow or peripheral blood stem cell graft without causing stem cell damage through the use of a conditionally replicative adenovirus (Ad). ES and NB are sensitive to Ad infection, and advanced NBs express a high level of the growth/differentiation factor midkine (MK). We confirmed in this study that ES cell lines (SK-ES-1 and RD-ES) are also sensitive to Ad infection and express high levels of MK. In contrast, CD34+ stem cells are refractory to Ad infection and express very little MK. A conditionally replicative Ad in which the expression of E1 is controlled by the MK promoter achieved good levels of viral replication in NB or ES and induced remarkable tumor cell killing. On the other hand, this virus caused no damage to CD34+ cells even after 3 h of infection at a dose of 1000 multiplicity of infection. We concluded that application of this replication-competent Ad to hematopoietic grafts could be a simple but effective procedure to achieve complete tumor cell purging.