Lala P K, Parhar R S
Department of Anatomy, University of Western Ontario, London, Canada.
Cancer Res. 1988 Mar 1;48(5):1072-9.
We had earlier shown that a single round of interleukin 2 (IL-2) in chronically indomethacin treated mice can totally or nearly totally ameliorate established, experimental lung metastases and reactivate natural killer (NK) and lymphokine activated killer-like cells in the spleen. The present study examined whether a lasting cure of metastasis is obtainable by chronic indomethacin therapy (CIT) combined with single or multiple rounds of IL-2, and if so, what are the morphological, phenotypic, and functional properties of tumoricidal cells generated in situ. Experimental lung metastasis was produced in B6 mice by an i.v. injection of 10(6) B16F10 melanoma cells to compare therapeutic effects of six protocols: (a) CIT (14 micrograms/ml via drinking water) starting on day 5 when pulmonary micrometastases are well established; (b) CIT combined with a single round of IL-2 (25,000 units, i.p., every 8 h for 5 days on days 10 through 14); (c) CIT combined with two rounds of IL-2 (days 10-14 and 20-24); (d) two rounds of IL-2 alone; (e) two rounds of IL-2 plus indomethacin given only during the IL-2 therapy; and (f) which was similar to (c), but in addition, followed by repeated injections of IL-2 (25,000 units twice a day on Mondays and Fridays for 8 consecutive weeks). Results revealed that chronic indomethacin therapy alone or two rounds of IL-2 alone, or two rounds of IL-2 plus discontinuous indomethacin therapy reduced the lung metastases (examined at 21-25 days) by about two-thirds. In contrast, both single and multiple rounds of IL-2 in chronically indomethacin treated mice totally or nearly totally eradicated the lung metastases. However, long-term disease-free survival (greater than 13-16 months) resulted only with multiple rounds of IL-2. With chronic indomethacin therapy alone, NK-like (AGM-1+, Thy-1-,Lyt-2-) killer lymphocytes (capable of killing NK sensitive YAC-1 lymphoma and B16F10 melanoma targets) appeared in the spleen, but not lungs; no killer activity was generated in macrophages at either site. Addition of a single round of IL-2 generated lymphokine activated killer-like killer lymphocytes (also capable of killing an NK resistant target) of the same phenotype, but of higher activity in the spleen; some lymphokine activated killer-like killer function was generated among pulmonary lymphocytes which were AGM-1+, Thy-1+,Lyt-2-, as well as among splenic but not pulmonary macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)
我们之前已经表明，在长期接受吲哚美辛治疗的小鼠中，单次注射白细胞介素2（IL-2）能够完全或几乎完全改善已形成的实验性肺转移，并使脾脏中的自然杀伤（NK）细胞和淋巴因子激活的杀伤样细胞重新激活。本研究探讨了慢性吲哚美辛治疗（CIT）联合单次或多次IL-2注射是否能实现转移的持久治愈，如果可以，原位产生的杀肿瘤细胞的形态、表型和功能特性是什么。通过静脉注射10(6)个B16F10黑色素瘤细胞在B6小鼠中产生实验性肺转移，以比较六种方案的治疗效果：（a）在肺微转移充分形成的第5天开始进行CIT（通过饮用水给予14微克/毫升）；（b）CIT联合单次IL-2注射（25,000单位，腹腔注射，每8小时一次，在第10至14天共5天）；（c）CIT联合两次IL-2注射（第10 - 14天和第20 - 24天）；（d）单独两次IL-2注射；（e）仅在IL-2治疗期间给予两次IL-2加吲哚美辛；（f）与（c）相似，但此外，随后连续8周每周一和周五每天两次重复注射IL-2（25,000单位）。结果显示，单独慢性吲哚美辛治疗、单独两次IL-2注射或两次IL-2加间断吲哚美辛治疗可使肺转移（在21 - 25天检查）减少约三分之二。相比之下，在长期接受吲哚美辛治疗的小鼠中，单次和多次IL-2注射都能完全或几乎完全消除肺转移。然而，只有多次IL-2注射才能实现长期无病生存（大于13 - 16个月）。单独慢性吲哚美辛治疗时，脾脏中出现了NK样（AGM-1 +、Thy-1 -、Lyt-2 -）杀伤淋巴细胞（能够杀伤对NK敏感的YAC-1淋巴瘤和B16F10黑色素瘤靶标），但肺中没有；两个部位的巨噬细胞均未产生杀伤活性。添加单次IL-2注射可产生相同表型的淋巴因子激活的杀伤样杀伤淋巴细胞（也能够杀伤NK抗性靶标），但在脾脏中的活性更高；在AGM-1 +、Thy-1 +、Lyt-2 -的肺淋巴细胞以及脾脏而非肺巨噬细胞中产生了一些淋巴因子激活的杀伤样杀伤功能。（摘要截断于400字）
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