Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy.
Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy.
复制标题
DOI：
10.1186/1479-5876-9-77
复制
发表时间：
2011-05-25
影响因子：
7.4
通讯作者：
Coukos G
中科院分区：
文献类型：
--
作者：
Alagkiozidis I;Facciabene A;Tsiatas M;Carpenito C;Benencia F;Adams S;Jonak Z;June CH;Powell DJ Jr;Coukos G
时间依赖性化疗剂可以选择性地靶向处于细胞周期的敏感期的肿瘤细胞，然而处于非脆弱细胞周期期的一部分肿瘤细胞仍然具有耐药性。免疫治疗是克服阶段特异性药物的局限性和提高其临床疗效的一种有前途的方法。在这里，我们研究了抗癌化疗药物与IL-18（一种具有强免疫刺激特性的细胞因子）联合使用的潜在用途。首先测试了卵巢癌中常用的四种化疗药物在体外增加小鼠卵巢癌细胞系ID 8的免疫原性和杀伤的能力。然后使用ID 8-Vegf卵巢癌模型测试具有测量的时间依赖性免疫增强作用的化疗剂与IL-18免疫疗法组合的体内抗肿瘤有效性。紫杉醇或拓扑替康暴露单独介导体外对小鼠卵巢癌细胞系ID 8的不完全、时间依赖性杀伤，而卡铂或吉西他滨介导全面、剂量依赖性杀伤。在托泊替康或紫杉醇的时间依赖性杀伤的平台期，耐药ID 8细胞具有更高的免疫原性，MHC-I和Fas的表达升高，并且对CTL和Fas激动性抗体的体外敏感性增加。此外，通过T细胞依赖性机制，加入IL-18后，时间依赖性药物的体内抗肿瘤有效性显著提高，而无显著时相特异性的药物的有效性则没有提高。使用IL-18的肿瘤免疫治疗可以显著增加时相特异性化疗药物的杀伤分数并提供生存益处。IL-18的安全性特征及其与选择的抗癌化疗剂的积极相互作用强烈支持这种组合方法的临床研究。
Time-dependent chemotherapeutic agents can selectively target tumor cells in susceptible phases of the cell cycle however a fraction of tumor cells in non-vulnerable cell cycle phases remain drug-resistant. Immunotherapy represents a promising approach to overcome the limitation of phase-specific drugs and improve their clinical efficacy. Here, we investigated the potential use of anticancer chemotherapeutic drugs in combination with IL-18, a cytokine with strong immunostimulatory properties. Four chemotherapeutic drugs commonly used in ovarian cancer were first tested for the ability to increase the immunogenicity and killing of the murine ovarian cancer cell line ID8 in vitro. Chemotherapeutric agents with measured time-dependent immune-enhancing effects were then tested for antitumor effectiveness in vivo in combination with IL-18 immunotherapy using the ID8-Vegf ovarian cancer model. Paclitaxel or topotecan exposure alone mediated incomplete, time-dependent killing against the murine ovarian cancer cell line ID8 in vitro, whereas carboplatin or gemcitabine mediated comprehensive, dose-dependent killing. In the plateau phase of the time-dependent killing by topotecan or paclitaxel, drug-resistant ID8 cells were more immunogenic with elevated expression of MHC-I and Fas, and increased sensitivity to CTL and Fas agonistic antibody in vitro. Moreover, the antitumor effectiveness of time-dependent agents in vivo was significantly improved with the addition of IL-18 through a T cell-dependent mechanism, while the effectiveness of drugs without significant phase specificity were not. Tumor immunotherapy with IL-18 can significantly augment the killing fraction of phase-specific chemotherapeutic drugs and provide survival benefit. The safety profile of IL-18 and its positive interactions with select anticancer chemotherapeutic agents strongly supports the clinical investigation of this combinatorial approach.
登录
查看更多内容
DOI：
10.1093/jnci/84.23.1816
发表时间：
1992-12-02
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
BURRIS, HA;HANAUSKE, AR;VONHOFF, DD
通讯作者：
VONHOFF, DD
DOI：
10.1073/pnas.93.22.12445
发表时间：
1996-10-29
影响因子：
11.1
作者：
Groh, V;Bahram, S;Spies, T
通讯作者：
Spies, T
影响因子：
45.3
作者：
Hoskins, P;Eisenhauer, E;Zee, B
通讯作者：
Zee, B
影响因子：
45.3
作者：
Correale, P;Cusi, MG;Francini, G
通讯作者：
Francini, G
影响因子：
3.9
作者：
Ciusani, E;Croci, D;Salmaggi, A
通讯作者：
Salmaggi, A