Duan Xiaoping, Jia Shu-Fang, Koshkina Nadezhda, Kleinerman Eugenie S
Division of Pediatrics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer. 2006 Mar 15;106(6):1382-8. doi: 10.1002/cncr.21744.
Cyclophosphamide (CTX) and ifosfamide (IFX) are alkylating agents used to treat osteosarcoma (OS). It was previously demonstrated that the sensitivity of OS cells to 4-hydroperoxycyclophosphamide (4-HC, the active metabolite of CTX) is augmented by interleukin (IL)-12 in vitro through a mechanism involving the Fas/FasL pathway. The purpose of these studies was to determine whether this synergistic effect is operational in vivo.
Mice were injected intravenously with human LM7 osteosarcoma cells. Treatment was initiated with IFX (2.5 mg/kg intraperitoneally) with or without intranasal polyethylenimine (PEI):IL-12 gene therapy given twice weekly for 6 weeks.
Expression of IL-12 protein in the lung was demonstrated in all mice receiving intranasal PEI:IL-12 but not in control mice or those treated with IFX alone. Increased expression of FasL was detected in lungs of all mice receiving IFX. Both IFX and PEI:IL-12 alone significantly inhibited lung metastasis when compared with control groups (P < 0.05). However, the most significant tumor effect was observed in mice receiving IFX+PEI:IL-12 (P < 0.01). Immunohistochemical staining for CD31 and basic fibroblast growth factor (bFGF) and the number of proliferating cells as quantified by proliferating cell nuclear antigen (PCNA) staining were also most significantly decreased in mice receiving combination therapy.
These data indicate that combining IFX and IL-12 may have therapeutic potential and that this increased efficacy may be mediated through a mechanism involving the Fas/FasL pathway.
环磷酰胺（CTX）和异环磷酰胺（IFX）是用于治疗骨肉瘤（OS）的烷化剂。先前已证明，在体外，白细胞介素（IL）-12通过涉及Fas/FasL途径的机制增强骨肉瘤细胞对4-氢过氧环磷酰胺（4-HC，CTX的活性代谢产物）的敏感性。这些研究的目的是确定这种协同作用在体内是否起作用。
给小鼠静脉注射人LM7骨肉瘤细胞。用IFX（2.5mg/kg腹腔注射）开始治疗，同时或不同时进行每周两次、持续6周的鼻内聚乙烯亚胺（PEI）：IL-12基因治疗。
在所有接受鼻内PEI：IL-12的小鼠的肺中均证实有IL-12蛋白表达，而在对照小鼠或仅接受IFX治疗的小鼠中未检测到。在所有接受IFX的小鼠的肺中检测到FasL表达增加。与对照组相比，单独使用IFX和PEI：IL-12均显著抑制肺转移（P<0.05）。然而，在接受IFX+PEI：IL-12的小鼠中观察到最显著的肿瘤效应（P<0.01）。在接受联合治疗的小鼠中，CD31和碱性成纤维细胞生长因子（bFGF）的免疫组织化学染色以及通过增殖细胞核抗原（PCNA）染色定量的增殖细胞数量也显著减少。
这些数据表明，联合使用IFX和IL-12可能具有治疗潜力，并且这种增强的疗效可能通过涉及Fas/FasL途径的机制介导。
