Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
J Transl Med. 2009 Dec 10;7:104. doi: 10.1186/1479-5876-7-104.
Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.
Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack in vitro. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated in vivo in mice bearing ID8-Vegf tumors.
While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death in vitro. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy in vivo and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.
These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 in vivo.
脂质体阿霉素（Doxil）是一种细胞毒性化疗药物，具有良好的血液学毒性特征。其活性药物阿霉素具有有趣的免疫调节特性。在这里，研究了 Doxil 对存活肿瘤细胞免疫表型的影响。
使用 ID8 小鼠卵巢癌细胞，通过测量 Doxil 对卵巢癌细胞 MHC 类-I 和 Fas 表达的影响以及体外对免疫攻击的敏感性，研究 Doxil 的免疫调节作用。为了评估 Doxil 与癌症免疫治疗合作的能力，在携带 ID8-Vegf 肿瘤的小鼠体内研究了 Doxil 与白细胞介素 18（IL-18）之间的相互作用，白细胞介素 18 是一种多效免疫刺激细胞因子。
虽然 Doxil 以剂量依赖性方式杀死 ID8 肿瘤细胞，但逃避 Doxil 诱导凋亡的肿瘤细胞上调了表面 MHC-I 和 Fas 的表达，并且在体外对 CTL 杀伤和 Fas 介导的死亡敏感。因此，我们测试了这样一个假设，即免疫治疗与 Doxil 的联合提供了积极的相互作用。组合 IL-18 和 Doxil 与单独使用任何一种药物相比，在体内显著抑制肿瘤生长，并且独特地导致一部分小鼠的肿瘤完全消退和长期抗肿瘤保护。
这些数据表明，Doxil 有利地改变了大量逃避直接杀伤的肿瘤的免疫表型，从而为免疫治疗扩大肿瘤杀伤创造了机会，通过体内添加 IL-18 可以利用这一机会。
