Fujimaki W, Griffin J R, Kleinerman E S
Department of Cell Biology (HMB 173), University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cancer Immunol Immunother. 1993;36(1):45-51. doi: 10.1007/BF01789130.
The purpose of this study was to determine the effects of ibuprofen on the ability of liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) to activate human blood monocytes in vitro. We undertook these experiments because the major toxic side-effects following L-MTP-PE infusion, fever and chills, could be prevented when ibuprofen was given orally immediately before L-MTP-PE infusion. It was therefore important to determine whether ibuprofen interfered with the macrophage-activation properties of L-MTP-PE. Peripheral blood monocytes were isolated from normal donors, then incubated with L-MTP-PE in the presence or absence of ibuprofen. The cytotoxic properties of the monocytes were assessed by a radioisotope-release assay against A375 cells. Ibuprofen at dose levels of 40 micrograms/ml suppressed the generation of the cytotoxic phenotype but did not interfere with the killing process once the cells were activated. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) production, as well as the mRNA expression of these cytokines, was suppressed by 40 micrograms/ml ibuprofen. Since IL-1 and TNF play a crucial role in the cytotoxic function of monocytes, these findings may explain the mechanism by which ibuprofen inhibited the generation of the cytotoxic phenotype by L-MTP-PE. By contrast, ibuprofen dose levels up to 10 micrograms/ml had no effect on the generation of monocyte-mediated cytotoxicity by L-MTP-PE and no effect on the production, secretion, or mRNA expression of TNF and IL-1. Therefore, we concluded that if ibuprofen is to be used to control the side-effects of L-MTP-PE, blood levels of up to 10 micrograms/ml are desirable. In two of three patients, we determined that an oral dose of 200 mg given immediately before L-MTP-PE infusion could achieve these desired blood levels.
本研究的目的是确定布洛芬对脂质体包裹的胞壁酰三肽磷脂酰乙醇胺（L-MTP-PE）体外激活人血单核细胞能力的影响。我们进行这些实验是因为在L-MTP-PE输注前立即口服布洛芬可预防L-MTP-PE输注后的主要毒副作用，即发热和寒战。因此，确定布洛芬是否会干扰L-MTP-PE的巨噬细胞激活特性很重要。从正常供体中分离外周血单核细胞，然后在有或无布洛芬的情况下与L-MTP-PE一起孵育。通过针对A375细胞的放射性同位素释放试验评估单核细胞的细胞毒性特性。剂量为40微克/毫升的布洛芬抑制了细胞毒性表型的产生，但一旦细胞被激活，并不干扰杀伤过程。40微克/毫升的布洛芬抑制了白细胞介素-1（IL-1）和肿瘤坏死因子α（TNFα）的产生以及这些细胞因子的mRNA表达。由于IL-1和TNF在单核细胞的细胞毒性功能中起关键作用，这些发现可能解释了布洛芬抑制L-MTP-PE产生细胞毒性表型的机制。相比之下，高达10微克/毫升的布洛芬剂量对L-MTP-PE介导的单核细胞细胞毒性的产生没有影响，对TNF和IL-1的产生、分泌或mRNA表达也没有影响。因此，我们得出结论，如果要用布洛芬来控制L-MTP-PE的副作用，理想的血药浓度应高达10微克/毫升。在三名患者中的两名中，我们确定在L-MTP-PE输注前立即口服200毫克的剂量可以达到这些理想的血药浓度。
