Agah R, Malloy B, Sherrod A, Bean P, Girgis E, Mazumder A
Norris Cancer Hospital and Research Institute, University of Southern California, School of Medicine, Los Angeles 90033.
J Biol Response Mod. 1988 Apr;7(2):140-51.
Tumor necrosis factor and interleukin-2 each in recombinant form have antitumor activity against established tumors if used in high enough dosages. The problem associated with such high dosages is the high degree of toxicity and expense encountered. Therefore, this study was undertaken to look at the antitumor efficacy of these two lymphokines when used together at dosages well below the toxic levels. Our results using recombinant human interleukin-2 (IL-2) and recombinant human tumor necrosis factor (TNF) against established methylcholanthrene-induced fibrosarcoma (MCA sarcoma) pulmonary metastases showed that TNF and IL-2 therapy at low nontoxic dosages alone did not produce significant tumor regression, but when combined at the same dosage synergize producing significant antitumor effects in mice induced with MCA sarcoma. This was also evident from histopathological examination of the lungs where the maximum tumor reduction along with the maximum lymphocytic infiltration into tumor was seen when TNF and IL-2 were combined. In this tumor regression, inherent immunity of the treated mice was needed, since in those mice in which we induced immunosuppression by using radiation, tumor regression was not seen when TNF and IL-2 therapy was combined in the doses efficacious in immunocompetent mice. Tumor regression is also dependent on the sequence of administration of IL-2 and TNF, since when IL-2 was administered before TNF, the tumor regression was more significant than when TNF was administered before IL-2 or when both were administered simultaneously to mice with established pulmonary tumors. Therefore the synergistic effect of IL-2 and TNF could be used as an efficacious but inexpensive and nontoxic alternative to therapy with lymphokine activated killer (LAK) cells + IL-2.
重组形式的肿瘤坏死因子和白细胞介素-2如果使用足够高的剂量，对已形成的肿瘤均具有抗肿瘤活性。与如此高剂量相关的问题是会遇到高度的毒性和高昂的费用。因此，本研究旨在观察这两种淋巴因子在远低于毒性水平的剂量下联合使用时的抗肿瘤疗效。我们使用重组人白细胞介素-2（IL-2）和重组人肿瘤坏死因子（TNF）对抗已形成的甲基胆蒽诱导的纤维肉瘤（MCA肉瘤）肺转移的结果表明，单独使用低无毒剂量的TNF和IL-2治疗不会产生显著的肿瘤消退，但当以相同剂量联合使用时，对MCA肉瘤诱导的小鼠具有协同作用，产生显著的抗肿瘤效果。这在对肺的组织病理学检查中也很明显，当TNF和IL-2联合使用时，可见最大程度的肿瘤缩小以及最大程度的淋巴细胞浸润到肿瘤中。在这种肿瘤消退过程中，需要治疗小鼠的固有免疫力，因为在那些我们通过辐射诱导免疫抑制的小鼠中，当TNF和IL-2治疗以在免疫活性小鼠中有效的剂量联合使用时，未见肿瘤消退。肿瘤消退还取决于IL-2和TNF的给药顺序，因为当IL-2在TNF之前给药时，肿瘤消退比TNF在IL-2之前给药或两者同时给药给已形成肺部肿瘤的小鼠时更显著。因此，IL-2和TNF的协同作用可作为一种有效但廉价且无毒的替代方案，用于替代淋巴因子激活的杀伤（LAK）细胞+IL-2疗法。
