Combination of local, nonviral IL12 gene therapy and systemic paclitaxel treatment in a metastatic breast cancer model
Combination of local, nonviral IL12 gene therapy and systemic paclitaxel treatment in a metastatic breast cancer model
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DOI：
10.1016/j.ymthe.2004.03.015
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发表时间：
2004-06-01
影响因子：
12.4
通讯作者：
Kim, SW
中科院分区：
文献类型：
--
作者：
Janát-Amsbury, MM;Yockman, JW;Kim, SW
重复的局部非病毒IL-12（白细胞介素-12）基因递送降低了肿瘤进展并增加了免疫原性。我们将我们的IL 12基因递送与全身紫杉醇化疗相结合，作为紫杉醇（PCT）耐药的4 T1皮下小鼠乳腺癌和PCT敏感的免疫原性/非免疫原性肿瘤的治疗。我们将PCT与可生物降解的聚合物增溶剂HySolv或Cremophor EL混合，用于每两个月一次的全身治疗，并每周局部注射水溶性脂聚合物（WSLP）/p2CMVmIL-12（编码IL 12基因的质粒）复合物。我们比较了治疗组和对照组的皮下肿瘤体积和肺转移。与Cremophor EL与WSLP/p2CMVmIL-12的组合相比，HySolv单独表现更好。与对照组和仅紫杉醇治疗组相比，我们显示了在组合的WSLP/p2CMVmIL-12/HySolv组中4 T1肿瘤生长和肺转移的抑制。在平行实验中，我们还证明了使用该组合策略的其他PCT敏感性乳腺肿瘤模型中肿瘤生长和肺转移数量的加性反应。我们的联合治疗为改进的药物递送系统的有效性和可行性提供了证据。局部细胞因子基因递送可以增强局部和全身化疗，而不会使宿主处于进一步全身毒性的风险中。
Repeated, local, nonviral IL12 (interleukin-12) gene delivery decreased tumor progression and increased immunogenicity. We combined our IL12 gene delivery with systemic paclitaxel chemotherapy as a treatment for paclitaxel (PCT)-resistant 4T1 subcutaneous mouse mammary carcinomas and PCT-sensitive, immunogenic/nonimmunogenic tumors. We mixed PCT with either a biodegradable polymeric solubilizer, HySolv, or Cremophor EL for bimonthly systemic treatments and injected water-soluble lipopolymer (WSLP)/p2CMVmIL-12 (plasmid encoding IL12 gene) complexes locally every week. We compared treated subcutaneous tumor volume and lung metastasis with controls. HySolv alone performed better compared to Cremophor EL in combination with WSLP/p2CMVmIL-12. We showed inhibition of 4T1 tumor growth and lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the paclitaxel-only treated groups. In parallel experiments we also demonstrated additive responses for tumor growth and number of lung metastases within other PCT-sensitive mammary tumor models using this combination strategy. Our combination therapy provides evidence for the efficacy and feasibility of improved drug delivery systems. Local cytokine gene delivery can augment local and systemic chemotherapy without placing the host at risk for further systemic toxicity.