Mullins D W, Walker T M, Burger C J, Elgert K D
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406, USA.
Cancer Immunol Immunother. 1997 Oct;45(1):20-8. doi: 10.1007/s002620050396.
The anticancer drug taxol (paclitaxel) inhibits tumors through multiple cytotoxic and cytostatic mechanisms. Independently of these mechanisms, taxol induces distinct immunological efficacy when it acts as a second signal for activation of tumoricidal activity by interferon gamma (IFN gamma)-primed murine normal host macrophages. We reported that tumor-distal macrophages, which mediate immunosuppression through dysregulated nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha) production, are differentially regulated by taxol. Because taxol influences tumor cell growth dynamics and activates immune cell populations, we assessed the ex vivo immunosuppressive and antitumor activities of taxol-treated normal host and tumor-bearing host (TBH) macrophages. Pretreatment of such cells with taxol partly reconstituted T cell alloantigen reactivity, suggesting that taxol mediates a limited reversal of TBH macrophage immunosuppressive activity. Taxol-treated TBH macrophages significantly suppressed the growth of fibrosarcoma cells (Meth-KDE) through soluble effector molecules and promoted direct cell-mediated cytotoxicity, indicating that taxol enhanced tumor-induced macrophage antitumor activities. Tumor-induced helper T cells, however, showed a higher sensitivity to direct taxol-induced suppression. These data demonstrate that taxol exerts pleiotropic effects on antitumor immune responses with the capacity to abate the immunosuppressive activities of macrophages and promote macrophage-mediated antitumor activities simultaneously, but also directly modulating T cell reactivity. Collectively, these studies suggest that the antineoplastic drug taxol may impart antitumor activity through an immunotherapeutic capacity.
抗癌药物紫杉醇通过多种细胞毒性和细胞生长抑制机制抑制肿瘤。独立于这些机制之外，当紫杉醇作为干扰素γ（IFNγ）预处理的小鼠正常宿主巨噬细胞激活杀肿瘤活性的第二信号时，它会诱导出独特的免疫效应。我们报道过，通过失调的一氧化氮（NO）和肿瘤坏死因子α（TNFα）产生介导免疫抑制的肿瘤远端巨噬细胞，受到紫杉醇的差异性调节。由于紫杉醇会影响肿瘤细胞的生长动态并激活免疫细胞群体，我们评估了经紫杉醇处理的正常宿主和荷瘤宿主（TBH）巨噬细胞的体外免疫抑制和抗肿瘤活性。用紫杉醇预处理此类细胞可部分恢复T细胞同种异体抗原反应性，这表明紫杉醇介导了TBH巨噬细胞免疫抑制活性的有限逆转。经紫杉醇处理的TBH巨噬细胞通过可溶性效应分子显著抑制了纤维肉瘤细胞（Meth-KDE）的生长，并促进了直接的细胞介导的细胞毒性，这表明紫杉醇增强了肿瘤诱导的巨噬细胞抗肿瘤活性。然而，肿瘤诱导的辅助性T细胞对紫杉醇直接诱导的抑制表现出更高的敏感性。这些数据表明，紫杉醇对抗肿瘤免疫反应具有多效性作用，能够减弱巨噬细胞的免疫抑制活性并同时促进巨噬细胞介导的抗肿瘤活性，而且还能直接调节T细胞反应性。总的来说，这些研究表明抗肿瘤药物紫杉醇可能通过免疫治疗能力赋予抗肿瘤活性。
