Pastorino Fabio, Di Paolo Daniela, Piccardi Federica, Nico Beatrice, Ribatti Domenico, Daga Antonio, Baio Gabriella, Neumaier Carlo E, Brignole Chiara, Loi Monica, Marimpietri Danilo, Pagnan Gabriella, Cilli Michele, Lepekhin Eugene A, Garde Seema V, Longhi Renato, Corti Angelo, Allen Theresa M, Wu Jinzi J, Ponzoni Mirco
Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
Clin Cancer Res. 2008 Nov 15;14(22):7320-9. doi: 10.1158/1078-0432.CCR-08-0804.
In vivo evaluation of good manufacturing practice-grade targeted liposomal doxorubicin (TVT-DOX), bound to a CD13 isoform expressed on the vasculature of solid tumors, in human tumor xenografts of neuroblastoma, ovarian cancer, and lung cancer.
Mice were implanted with lung, ovarian, or neuroblastoma tumor cells via the pulmonary, peritoneal, or orthotopic (adrenal gland) routes, respectively, and treated, at different days post inoculation, with multiple doses of doxorubicin, administered either free or encapsulated in untargeted liposomes (Caelyx) or in TVT-DOX. The effect of TVT-DOX treatment on tumor cell proliferation, viability, apoptosis, and angiogenesis was studied by immunohistochemical analyses of neoplastic tissues and using the chick embryo chorioallantoic membrane assay.
Compared with the three control groups (no doxorubicin, free doxorubicin, or Caelyx), statistically significant improvements in survival was seen in all three animal models following treatment with 5 mg/kg (maximum tolerated dose) of TVT-DOX, with long-term survivors occurring in the neuroblastoma group; increased survival was also seen at a dose of 1.7 mg/kg in mice bearing neuroblastoma or ovarian cancer. Minimal residual disease after surgical removal of neuroblastoma primary mass, and the enhanced response to TVT-DOX, was visualized and quantified by bioluminescence imaging and with magnetic resonance imaging. When treated with TVT-DOX, compared with Caelyx, all three tumor models, as assayed by immunohistochemistry and chorioallantoic membrane, showed statistically significant reductions in cell proliferation, blood vessel density, and microvessel area, showing increased cell apoptosis.
TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.
在人神经母细胞瘤、卵巢癌和肺癌的肿瘤异种移植模型中，对与实体瘤血管上表达的CD13亚型结合的药品生产质量管理规范级靶向脂质体阿霉素（TVT-DOX）进行体内评估。
分别通过肺内、腹腔内或原位（肾上腺）途径给小鼠植入肺癌、卵巢癌或神经母细胞瘤细胞，并在接种后的不同天数，用多剂量的阿霉素进行治疗，阿霉素可以是游离形式，也可以封装在非靶向脂质体（楷莱）或TVT-DOX中。通过对肿瘤组织进行免疫组织化学分析，并使用鸡胚绒毛尿囊膜试验，研究TVT-DOX治疗对肿瘤细胞增殖、活力、凋亡和血管生成的影响。
与三个对照组（无阿霉素、游离阿霉素或楷莱）相比，在使用5mg/kg（最大耐受剂量）的TVT-DOX治疗后，所有三个动物模型的生存率均有统计学意义的显著提高，神经母细胞瘤组出现了长期存活者；在携带神经母细胞瘤或卵巢癌的小鼠中，1.7mg/kg的剂量也观察到了生存率的提高。通过生物发光成像和磁共振成像对神经母细胞瘤原发肿块手术切除后的微小残留病灶以及对TVT-DOX的增强反应进行了可视化和定量分析。当用TVT-DOX治疗时，与楷莱相比，通过免疫组织化学和绒毛尿囊膜检测的所有三个肿瘤模型均显示细胞增殖、血管密度和微血管面积有统计学意义的显著降低，细胞凋亡增加。
TVT-DOX应作为实体瘤辅助治疗的一种新型血管生成抑制策略进行评估。
