Mullins D W, Burger C J, Elgert K D
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406, USA.
Int J Immunopharmacol. 1998 Oct;20(10):537-51. doi: 10.1016/s0192-0561(98)00047-2.
The antineoplastic agent paclitaxel (Taxol) mimics bacterial lipopolysaccharide (LPS) in normal host macrophages (Mphis), enhancing antitumor cytotoxicity in vitro. Because paclitaxel is used as an antitumor chemotherapeutic agent and tumor growth alters Mphi phenotype and function, we assessed effector molecule production and cytotoxic activity by normal host and tumor-bearing host (TBH) Mphis following paclitaxel administration. Paclitaxel treatment, duplicating human chemotherapeutic regimens, primed normal host splenic Mphis for enhanced production of the cytotoxic mediator nitric oxide (NO); in contrast, paclitaxel's NO-inducing activity was significantly suppressed in TBHs. In contrast to NO regulation, Mphi capacity for tumor necrosis factor-alpha (TNF-alpha) production in both normal hosts and TBHs was enhanced by paclitaxel administration. Although tumor growth modulated paclitaxel-induced Mphi NO production, paclitaxel administration enhanced both normal host and TBH Mphi cytotoxic antitumor activity. Blocking NO with a competitive inhibitor abrogated Mphi cytotoxicity, suggesting paclitaxel-induced TBH Mphi NO production, although suboptimal, remains sufficient to mediate antitumor activity. These data demonstrate that paclitaxel's in vivo immune activities are differentially regulated during tumor burden and suggest that paclitaxel's immunotherapeutic functions may contribute to its success as an anticancer agent.
抗肿瘤药物紫杉醇（泰素）在正常宿主巨噬细胞（Mphis）中模拟细菌脂多糖（LPS），在体外增强抗肿瘤细胞毒性。由于紫杉醇用作抗肿瘤化疗药物，且肿瘤生长会改变巨噬细胞的表型和功能，因此我们评估了紫杉醇给药后正常宿主和荷瘤宿主（TBH）巨噬细胞的效应分子产生及细胞毒性活性。按照人类化疗方案进行的紫杉醇治疗，使正常宿主脾脏巨噬细胞做好准备，以增强细胞毒性介质一氧化氮（NO）的产生；相比之下，紫杉醇诱导NO的活性在荷瘤宿主中显著受到抑制。与NO调节相反，紫杉醇给药增强了正常宿主和荷瘤宿主巨噬细胞产生肿瘤坏死因子-α（TNF-α）的能力。尽管肿瘤生长调节了紫杉醇诱导的巨噬细胞NO产生，但紫杉醇给药增强了正常宿主和荷瘤宿主巨噬细胞的细胞毒性抗肿瘤活性。用竞争性抑制剂阻断NO可消除巨噬细胞的细胞毒性，这表明紫杉醇诱导的荷瘤宿主巨噬细胞NO产生虽然未达最佳水平，但仍足以介导抗肿瘤活性。这些数据表明，紫杉醇的体内免疫活性在肿瘤负荷期间受到不同调节，提示紫杉醇的免疫治疗功能可能有助于其作为抗癌药物取得成功。
