ERADICATION OF SPONTANEOUS AND EXPERIMENTAL ADENOCARCINOMA METASTASES WITH CHRONIC INDOMETHACIN AND INTERMITTENT IL-2 THERAPY
ERADICATION OF SPONTANEOUS AND EXPERIMENTAL ADENOCARCINOMA METASTASES WITH CHRONIC INDOMETHACIN AND INTERMITTENT IL-2 THERAPY
复制标题
DOI：
10.1002/ijc.2910540425
复制
发表时间：
1993-06-19
影响因子：
6.4
通讯作者：
PARHAR, RS
中科院分区：
文献类型：
--
作者：
LALA, PK;PARHAR, RS
我们先前已经证明，荷瘤导致宿主巨噬细胞来源的PGE 2使IL-2依赖性效应细胞失活，并且旨在阻断前列腺素合成的慢性吲哚美辛治疗（CIT）结合多轮IL-2可以治愈小鼠多种肿瘤的实验性转移。我们现在已经测试了这种疗法对C3 H/HeJ小鼠中C3-LS乳腺癌的自发性以及实验性转移的功效。小鼠皮下移植C3-LS细胞（并且在第7天和第10天之间显示可见的自发性肺转移）的受试者从第15天开始给予CIT，加上2轮5天的IL-2或单独的IL-2。静脉内注射10（4）个C3-LS细胞（并且在第5天显示肺微转移）的小鼠在第5天被置于CIT上，并且给予3轮5天的IL-2或单独用IL-2治疗。对照小鼠仅接受媒介物。结果显示，在自发转移模型中，CIT + IL-2联合治疗引起原发性肿瘤消退，在第25-35天肺转移评分显著降低，宿主存活显著延长（79%治愈）。在第210天用10（4）个肿瘤细胞静脉内再激发的存活者抵抗肿瘤生长。在实验转移模型中，这种疗法也显著减少了肺转移，延长了动物存活率（50%治愈）。在两种模型中，联合治疗导致脾和肺中存在具有AGM-1+、Lyt-2-和Thy-1+/-表型的高活性杀肿瘤（针对C3-L5和YAC-1淋巴瘤靶点）淋巴细胞和巨噬细胞，以及血清中的ADCC促进活性。因此，CIT + IL-2治疗可以有效地根除小鼠中的自发性和实验性乳腺癌转移。它原位激活天然效应细胞，在血清中产生ADCC促进活性，并在这种中等免疫原性肿瘤模型中导致对肿瘤摄取的抗性。(C)1993 Wiley-Liss，Inc.
We had earlier shown that tumor-bearing results in an inactivation of IL-2-dependent effector cells by host macrophage-derived PGE2, and that chronic indomethacin therapy (CIT) aimed at blocking prostaglandin synthesis, combined with multiple rounds of IL-2, can cure experimental metastases of a variety of tumors in mice. We have now tested the efficacy of this therapy on spontaneous as well as experimental metastasis of C3-LS mammary adenocarcinoma in C3H/HeJ mice. Mice transplanted s.c. with C3-LS cells (and showing visible spontaneous lung metastases between days 7 and 10) were given CIT starting on day 1S, plus 2 5-day rounds of IL-2 or IL-2 alone. Mice injected i.v. with 10(4) C3-LS cells (and showing lung micrometastases on day 5) were placed on CIT on day 5 and given 3 5-day rounds of IL-2 or treated with IL-2 alone. Control mice received vehicles alone. Results revealed that combined CIT + IL-2 therapy in the spontaneous metastasis model caused a regression of primary tumors, a marked reduction in lung metastases scored on days 25-35 and a marked prolongation of host survival (79% cured). Survivors rechallenged with 10(4) tumor cells i.v. on day 2 1 0 resisted tumor growth. In the experimental metastasis model, this therapy also markedly reduced lung metastases and prolonged animal survival (50% cured). In both models, the combination therapy led to the presence of highly active tumoricidal (for C3-L5 and YAC-1 lymphoma targets) lymphocytes with AGM-1+, Lyt-2- and Thy-1+/- phenotype and macrophages in the spleen and the lungs, and ADCC-promoting activity in the serum. CIT + IL-2 therapy can thus effectively eradicate spontaneous and experimental mammary adenocarcinoma metastasis in mice. It activates natural effector cells in situ, generates ADCC-promoting activity in the serum and results in resistance to tumor take in this moderately immunogenic tumor model. (C) 1993 Wiley-Liss, Inc.