Induced proteins in human peripheral mononuclear cells over a range of clinically tolerable doses of interferon-gamma.
Induced proteins in human peripheral mononuclear cells over a range of clinically tolerable doses of interferon-gamma.
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在一系列临床可耐受剂量的干扰素-γ 下，在人外周单核细胞中诱导蛋白质。
DOI：
10.1089/jir.1989.9.457
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Borden,EC
中科院分区：
文献类型：
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作者：
Paulnock,DM;Havlin,KA;Storer,BM;Spear,GT;Sielaff,KM;Borden,EC
本研究评估了干扰素-γ (IFN-γ) 的三种不同剂量水平（0.15、1.5 和 15 mg/m2）的生物反应修改，每周 3 次静脉推注。最终共有 24 名患者进行评估。剂量限制性毒性发生在最高剂量水平（15 mg/m2），包括疲劳、白细胞减少和肝毒性。生物反应修饰的评估包括评估外周单核细胞中的2'，5'-寡腺苷酸（2-5A）合成酶活性，测量血清β2-微球蛋白和单核细胞上β2-微球蛋白的表达，测量单核细胞HLA II类表达（HLA-DR，HLA-DQ），以及测量第一次和第四次IFN-γ治疗后24小时单核细胞产生的过氧化氢。 24 小时时，除 H2O2 生成之外的所有参数均较基线显着增加 (p<0.05)。除了增强 HLA-DR 外，即使是最低剂量（0.15 mg/m2）也能增强 2-5A 合成酶和 HLA 蛋白的合成。血清和单核细胞 β2-微球蛋白水平的变化存在剂量反应效应，但 2-5A 合成酶水平或单核细胞上的 HLA II 类抗原表达没有变化。在 9 天内注射 4 剂后，大多数参数与治疗前相比仍然有所增加，但与第一次给药后达到的水平相比没有进一步增强。这项研究的结果证明了 IFN-γ 在宽剂量范围内对生物激活的功效，并且与生物治疗的免疫调节作用可以在人体中以远低于最大耐受剂量的剂量获得的假设相一致。需要进一步记录低剂量 IFN-γ 的生物反应参数，以确定生物激活与抗肿瘤活性相关的重要性。
This study assessed biologic response modification at three different dose levels (0.15, 1.5, and 15 mg/m2) of interferon-γ (IFN-γ) administered by intravenous bolus three times weekly. A final total of 24 patients were evaluable. Dose-limiting toxicity occurred at the highest dose level (15 mg/m2) and included fatigue, leukopenia, and hepatotoxicity. Evaluation of biologic response modification included assessment of 2′,5′-oligoadenylate (2-5A) synthetase activity in peripheral mononuclear cells, measurement of serum β2-microglobulin and expression of β2-microglobulin on monocytes, measurement of monocyte HLA Class II expression (HLA-DR, HLA-DQ), and measurement of hydrogen peroxide generation by monocytes 24 h after the first and fourth IFN-γ treatments. Significant increases (p< 0.05) from baseline were seen at 24 h with all parameters except H2O2generation. Except for enhancement of HLA-DR, even the lowest dose (0.15 mg/m2) augmented synthesis of 2-5A synthetase and HLA proteins. A dose-response effect was noted for changes in serum and monocyte β2-microglobulin levels but not for 2-5A synthetase levels or HLA Class II antigen expression on monocytes. After 4 doses administered over 9 days, most parameters remained increased when compared to pretreatment, but were not further enhanced when compared with levels attained after the first dose. The results of this study document the efficacy of IFN-γ for biological activation over a wide dose range and are consistent with the postulate that immunoregulatory effects of biological therapeutics can be obtained in man at doses substantially less than those that are maximally tolerated. Further documentation of biologic response parameters by IFN-γ at low doses will be necessary to determine the importance of biologic activation in relation to antitumor activity.