Mullins D W, Alleva D G, Burger C J, Elgert K D
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406, USA.
Immunopharmacology. 1997 Aug;37(1):63-73. doi: 10.1016/s0162-3109(97)00004-0.
Taxol, a potent antitumor chemotherapeutic, promotes in vitro cytotoxic antitumor activities by normal host macrophage (M phi s). Because tumor growth induces functional changes among M phi populations, we determined whether fibrosarcoma growth (Meth-KDE) modified M phi responsiveness to the activating agent taxol. Tumors induce tumor-distal M phi populations to become immune suppressor cells, partially through overproduction of the cytotoxic and proinflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Beneficial to the tumor-bearing host (TBH) when released by tumor-proximal M phi s, NO and TNF-alpha suppress lymphoproliferation and fail to impart antitumor activity when expressed in tumor-distal compartments. We report that taxol differentially regulated normal host and TBH M phi production of the immunosuppressive molecule NO by tumor-distal M phi populations. In response to IFN-gamma-priming and taxol triggering, TBH M phi s increase their production of NO as compared to resting M phi s; however, unlike normal host M phi s, taxol-induced TBH M phi NO production was significantly suboptimal. Modulation of TBH M phi NO production in tumor-distal compartments may alleviate M phi-mediated suppression of T-cell proliferative responses, yet promote sufficient NO production by tumor-associated M phi s to affect cytotoxicity. Collectively, these data leave implications for immunotherapeutic activities by the anticancer drug taxol.
紫杉醇是一种强效抗肿瘤化疗药物，可通过正常宿主巨噬细胞（Mφs）促进体外细胞毒性抗肿瘤活性。由于肿瘤生长会诱导Mφ群体发生功能变化，我们确定纤维肉瘤生长（Meth-KDE）是否会改变Mφ对激活剂紫杉醇的反应性。肿瘤会诱导肿瘤远端的Mφ群体成为免疫抑制细胞，部分原因是细胞毒性和促炎分子一氧化氮（NO）和肿瘤坏死因子-α（TNF-α）的过量产生。当由肿瘤近端的Mφ释放时，NO和TNF-α对荷瘤宿主（TBH）有益，但在肿瘤远端区域表达时，它们会抑制淋巴细胞增殖且无法赋予抗肿瘤活性。我们报告称，紫杉醇对肿瘤远端Mφ群体产生免疫抑制分子NO的正常宿主和TBH Mφ有不同的调节作用。与静息Mφ相比，在IFN-γ预处理和紫杉醇触发下，TBH Mφ会增加其NO的产生；然而，与正常宿主Mφ不同，紫杉醇诱导的TBH Mφ产生的NO明显未达最佳水平。调节肿瘤远端区域TBH Mφ产生的NO可能会减轻Mφ介导的对T细胞增殖反应的抑制，但同时促进肿瘤相关Mφ产生足够的NO以影响细胞毒性。总的来说，这些数据揭示了抗癌药物紫杉醇的免疫治疗活性。
