Galligioni E, Favaro D, Santarosa M, Quaia M, Spada A, Freschi A, Alberti D
Centro di Riferimento Oncologico, Aviano (PN), and Ciba-Geigy, Origgio (VA), Italy.
Clin Cancer Res. 1995 May;1(5):493-9.
Monocyte-mediated cytotoxicity (determined in a 72-h111In release assay) and the circulating levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1beta, IL-6, IFN-gamma, C-reactive protein, and beta2-microglobulin were determined in 14 melanoma patients treated with multilamellar vesicle liposomes containing muramyl tripeptide phosphatidylethanolamine, 4 mg twice a week for 12 weeks. Monocyte-mediated cytotoxicity increased 24 h after the first infusion in 9 of 14 patients and had reached maximum levels (mean, 44% +/- 8) in all patients by the sixth week; similar values were observed at the 12th week. Once increased in vivo, peripheral blood monocyte cytotoxicity was not susceptible to any further increase after a subsequent in vitro incubation of the monocytes with liposomes. However, the peripheral blood monocytes which were not cytotoxic in vivo were activated by in vitro incubation with liposomes and not by medium. TNF-alpha and IL-6 peaked 2 h after the first infusion and returned to baseline values at 24 h; they were not significantly increased by subsequent treatments. The induction of fever in patients, observed 2 h after the first infusion, correlated with TNF-alpha and IL-6 levels. Similarly, C-reactive protein levels also increased at 24 h, but only after the first dose. No increase in beta2-microglobulin and IL-1beta levels was observed, and IFN-gamma was never detected in serum. Two patients experienced stable disease lasting 7 and 12 months, and 12 patients progressed. These results show that multilamellar vesicle muramyl tripeptide phosphatidylethanolamine administration activates monocyte cytotoxicity and cytokine production (TNF-alpha, IL-6). Chronic treatment with multilamellar vesicle muramyl tripeptide phosphatidylethanolamine results in tachyphylaxis in terms of cytokine secretion but not cytotoxicity. There was no difference between the maximum cytotoxicity levels obtained in vivo and those obtained in vitro using the same agent. A better understanding of immunoregulation is required for a rational application of this and related immunotherapies.
在14例接受含胞壁酰三肽磷脂酰乙醇胺的多层脂质体治疗的黑色素瘤患者中，测定了单核细胞介导的细胞毒性（通过72小时铟-111释放试验确定）以及肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-1β、IL-6、干扰素-γ、C反应蛋白和β2-微球蛋白的循环水平。治疗方案为每周两次，每次4毫克，共12周。14例患者中有9例在首次输注后24小时单核细胞介导的细胞毒性增加，到第6周时所有患者均达到最高水平（平均为44%±8）；在第12周时观察到类似数值。外周血单核细胞在体内一旦被激活，随后将其与脂质体进行体外孵育后，其细胞毒性不会进一步增加。然而，体内无细胞毒性的外周血单核细胞经脂质体体外孵育后被激活，而经培养基孵育则未被激活。TNF-α和IL-6在首次输注后2小时达到峰值，并在24小时恢复至基线值；后续治疗未使其显著升高。首次输注后2小时观察到的患者发热与TNF-α和IL-6水平相关。同样，C反应蛋白水平在24小时时也升高，但仅在首次给药后出现。未观察到β2-微球蛋白和IL-1β水平升高，血清中也从未检测到干扰素-γ。2例患者病情稳定，持续7个月和12个月，12例患者病情进展。这些结果表明，给予多层脂质体胞壁酰三肽磷脂酰乙醇胺可激活单核细胞的细胞毒性和细胞因子产生（TNF-α、IL-6）。长期给予多层脂质体胞壁酰三肽磷脂酰乙醇胺在细胞因子分泌方面会导致快速减敏，但在细胞毒性方面不会。体内获得的最大细胞毒性水平与使用相同药物在体外获得的水平之间没有差异。为合理应用这种及相关免疫疗法，需要更好地理解免疫调节。
