Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2.
Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2.
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DOI：
10.1084/jem.161.5.1169
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发表时间：
1985-05-01
影响因子：
15.3
通讯作者：
Schwarz, S L
中科院分区：
文献类型：
--
作者：
Rosenberg, S A;Mule, J J;Spiess, P J;Reichert, C M;Schwarz, S L
静息淋巴样细胞与重组白细胞介素2 (IL-2)在体外孵育可产生淋巴因子激活杀伤(LAK)细胞，其能够在短期铬释放测定中裂解新鲜肿瘤细胞悬浮液。我们之前的研究（7）已经证明，注射LAK细胞加上低剂量的重组IL-2能够抑制肺转移瘤的生长。我们现在已经探索了全身施用高剂量重组IL-2在体内产生LAK细胞并直接介导抗肿瘤作用的能力。腹膜内施用增加剂量的重组IL-2导致受体小鼠的脾脏中产生LAK细胞。约每 8 小时腹腔内施用 100,000 U 重组 IL-2，持续 5 天，能够显着抑制 C57BL/6 小鼠中 MCA-105 和 MCA-106 同基因肉瘤以及同基因 B16 黑色素瘤已形成的 3 d 肺转移。肿瘤注射后 10 天出现的肉眼可见的转移也在 IL-2 治疗后出现消退。令人惊讶的是，已建立的 10 天肺转移瘤比较小的 3 天肺转移瘤更容易受到 IL-2 的影响。如果小鼠事先接受 500 rad 全身照射治疗，则全身施用重组 IL-2 的所有抗肿瘤作用都会被消除。高剂量重组IL-2的施用还能够抑制来自MCA-105肉瘤的3天建立的皮下肿瘤的生长，并介导对已建立的可触及皮下MCA-105肉瘤的生长和消退的抑制。形态学上表现出被激活的淋巴细胞存在于肿瘤消退的部位，全身施用重组IL-2的抗肿瘤作用的机制似乎是通过体内LAK细胞的产生，尽管这一假设仍有待证实。高剂量重组人 IL-2 的现成可用以及在动物模型中观察到的抗肿瘤作用的证明使我们开始了重组 IL-2 在人体中的临床试验。
Incubation of resting lymphoid cells with recombinant interleukin 2 (IL- 2) in vitro leads to the generation of lymphokine activated killer (LAK) cells capable of lysing fresh tumor cell suspensions in short- term chromium-release assays. Our previous studies (7) have demonstrated that the injection of LAK cells plus low doses of recombinant IL-2 were capable of inhibiting the growth of pulmonary metastases. We have now explored the ability of high doses of recombinant IL-2, administered systemically, to generate LAK cells in vivo, and to mediate antitumor effects directly. Administration of increasing doses of recombinant IL-2 intraperitoneally resulted in the generation of LAK cells in the spleens of recipient mice. Doses of 100,000 U recombinant IL-2 administered intraperitoneally approximately every 8 h for 5 d were capable of dramatically inhibiting established 3- d pulmonary metastases from the MCA-105 and MCA-106 syngeneic sarcomas and the syngeneic B16 melanoma in C57BL/6 mice. Grossly visible metastases present at 10 d after tumor injection also underwent regression following IL-2 therapy. Surprisingly, established 10 d pulmonary metastases were more susceptible to the effects of IL-2 than were the smaller 3 d pulmonary metastases. All antitumor effects of the systemic administration of recombinant IL-2 were eliminated if mice received prior treatment with 500 rad total body irradiation. The administration of high doses of recombinant IL-2 was also capable of inhibiting the growth of 3-d established subcutaneous tumors from the MCA-105 sarcoma, and of mediating the inhibition of growth and regression of established palpable subcutaneous MCA-105 sarcomas. Lymphocytes, which appeared morphologically to be activated, were present at the site of regressing tumor, and it appears that the mechanism of the antitumor effect of recombinant IL-2 administered systemically is via the generation of LAK cells in vivo, although this hypothesis remains to be proven. The ready availability of high doses of recombinant human IL-2, and the demonstration of antitumor effects seen in animal models have led us to the initiation of the clinical trials of recombinant IL-2 in humans.