Liposome and Polycationic Gene Therapy for Osteosarcoma

骨肉瘤的脂质体和聚阳离子基因治疗

基本信息

批准号：
7751217
负责人：
Eugenie S Kleinerman
金额：
$ 26.39万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-08-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7751217
关键词：
Adjuvant Chemotherapy Adolescent Adult Adverse effects Aerosol Drug Therapy Aerosols Cell Line Cell Proliferation Cells Chemotherapy-Oncologic Procedure Child Childhood Clinical Trials Coughing Data Death Domain Dominant-Negative Mutation Drug Delivery Systems Encapsulated Fatigue Genes Grant Host resistance Human In Vitro Interleukin-12 Interleukin-12 Gene Investigation Knockout Mice Laboratories Liposomes Lung Mediator of activation protein Metastatic Neoplasm to the Lung Metastatic Osteosarcoma Metastatic to Methods Microscopic Modeling Mus Neoplasm Metastasis New Agents Nitrocamptothecin Nude Mice Organ Pathway interactions Patients Phase Phase I Clinical Trials Play Pre-Clinical Model Relapse Role Signal Transduction Signal Transduction Pathway Site Sore Throat Stream System Therapeutic Toxic effect Treatment Efficacy Up-Regulation Wheezing base chemotherapy gene therapy in vivo metastatic process migration mouse model neoplastic cell novel novel strategies osteosarcoma overexpression response tumor vector young adult

项目摘要

Despite multiple changes in adujvant chemotherapy, the 2-year metastasis-free survival in osteosarcoma (OS) has remained stagnant at 65-70% for the past 10 years. The lung is the most common and often the only site of metastases. Our laboratory has focused on understanding the mechanisms involved in OS metastasis to the lung and in identifying novel ways to treat OS pulmonarymetastases. Using our experimental humanOS lung metastasis nude mouse model we demonstrated that Fas expression correlates inversely with metastatic potential. We hypothesized that because FasL is constitutively expressed in the lung, that OS cells expressing high levels of Fas will be eliminated upon migration into the lung, whereas those with low or no Fas expression will evade this form of host resistance. We also demonstrated that IL-12 upregulated tumor Fas expression in vitro, altered metastatic potential and that the IL-12 gene could be delivered by aerosol using polyethyinemine (PEI) as a vector delivery system. Aerosol PEI:IL-12 upregulated tumor Fas in vivo and induced regression of established microscopic pulmonary metastases. We also demonstrated that aerosol delivery of liposome-encapsulated 9-nitrocamptothecin (L-9NC) upregulated tumor Fas expression and resulted in eradication of OS lung metastases. A phase I trial in adults using aerosol L-9NC demonstrated the feasibility of aerosol chemotherapy. No children or adolescents were treated in this phase I trial. We now propose to (1) perform a phase I/II clinicaltrial with aerosol L-9NC in patients 10-25 years old with metastases in the lung; (2) determine whether inhibiting Fas signalling impacts tumor cell clearance, cell proliferation and the metastatic potential of OS cells to the lung; (3) determine whether the Fas pathway is critical for both aerosol IL-12 and L-9NC activity in vivo. Together these investigations should give an indication of the importance of the Fas pathway in the metastatic process of OS and in the therapeutic efficacy of both aerosol L-9NC and PEI:IL-12 gene therapy. The long term objectives are to develop aerosol therapy for metastatic OS and other tumors that relapse in the lung.

尽管辅助化疗发生了多次变化，但骨肉瘤 (OS) 的 2 年无转移生存率仍呈下降趋势。过去10年一直停滞在65-70%。肺部是最常见且通常是唯一的部位转移。我们的实验室致力于了解 OS 转移至肺部的机制以及确定治疗 OS 肺转移的新方法。使用我们的实验性 humanOS 裸肺转移我们在小鼠模型中证明 Fas 表达与转移潜能呈负相关。我们假设由于 FasL 在肺中持续表达，因此表达高水平 Fas 的 OS 细胞将迁移到肺部后被消除，而那些具有低或无 Fas 表达的人将逃避这种形式的宿主反抗。我们还证明 IL-12 在体外上调肿瘤 Fas 表达，改变转移潜能 IL-12 基因可以使用聚乙烯胺 (PEI) 作为载体传递系统通过气雾剂传递。气溶胶 PEI:IL-12 上调体内肿瘤 Fas 并诱导已建立的微观肺组织消退转移。我们还证明了脂质体封装的 9-硝基喜树碱 (L-9NC) 的气雾输送上调肿瘤 Fas 表达并导致 OS 肺转移的根除。在成人中进行的 I 期试验气雾剂L-9NC证明了气雾剂化疗的可行性。没有儿童或青少年在此接受治疗第一阶段试验。我们现在建议 (1) 在 10-25 岁患者中进行气雾剂 L-9NC 的 I/II 期临床试验肺部有转移； (2)确定抑制Fas信号传导是否影响肿瘤细胞清除、细胞 OS细胞的增殖和肺转移潜力； (3) 确定Fas通路是否至关重要气溶胶 IL-12 和 L-9NC 体内活性。这些调查一起应该表明 Fas 通路在 OS 转移过程和气雾剂 L-9NC 治疗功效中的重要性 PEI:IL-12 基因治疗。长期目标是开发用于转移性 OS 和其他疾病的气雾疗法肺部复发的肿瘤。