Freedman R S, Gibbons J A, Giedlin M, Kudelka A P, Kavanagh J J, Edwards C L, Carrasco C H, Nash M A, Platsoucas C D
Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
J Immunother Emphasis Tumor Immunol. 1996 Nov;19(6):443-51. doi: 10.1097/00002371-199611000-00009.
We determined in the peritoneal cavity (p.c.) of epithelial ovarian carcinoma patients during a 4-day treatment cycle of low-dose recombinant human interleukin-2 (rIL-2): (a) pharmacokinetics of IL-2, (b) endogenous cytokine production, and (c) numbers and percentages of peritoneal exudate lymphocytes. We administered 6 x 10(5) IU/m2 of rIL-2 (0.03 mg/m2 Proleukin rIL-2) intraperitoneally (i.p.) over 30 min on each of 4 days. One and one-half liters of D5 0.25 NS was injected i.p. before each rIL-2 infusion. Multiple peritoneal fluid samples were obtained from each of four patients on day 1 and day 4 for detection of IL-2, endogenous cytokines, and soluble IL-2 receptor (IL-2R-alpha). IL-2 concentrations in the peritoneal fluid were determined by bioassay and interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-10, transforming growth factor (TGF)-beta 2, and sIL-2R-alpha by enzyme-linked immunosorbent assay. Numbers of cells per microliter and lymphocyte subpopulation percentages after staining with a panel of monoclonal antibodies were determined on day 1, day 4, and subsequent off-treatment days. IL-2 disappearance in the p.c. was well described by a pharmacokinetic model having constant-rate infusion and biexponential disposition. About 90% of the IL-2 disappearance occurred during the beta-phase, during which IL-2 concentrations were sustained at approximately 10-30 ng/ml (day 1 and day 4) and the median t1/2 beta was 21.5 and 9.2 h on days 1 and 4, respectively. In four of four patients, p.c. production of IL-10 was observed on day 1 and day 4 (maximum 387 pg/ml). Maximum levels of IFN-gamma and sIL-2R-alpha were observed on day 4. (IFN-gamma 217 pg/ml; sIL2-R-alpha: 3486 U/ml). No increases in TNF-alpha or TGF-beta 2 were observed. Large increases in p.c. CD3+, CD4+, CD8+, CD16+, and CD56+ cells were observed. We conclude that biologically active levels of IL-2 are generated in p.c. fluids after i.p. administration of rIL-2 at 0.03 mg/m2.
我们在低剂量重组人白细胞介素-2（rIL-2）的4天治疗周期中，对上皮性卵巢癌患者的腹腔（p.c.）进行了研究，内容包括：（a）IL-2的药代动力学，（b）内源性细胞因子的产生，以及（c）腹腔渗出淋巴细胞的数量和百分比。我们在4天中的每一天，于30分钟内腹腔内（i.p.）给予6×10⁵IU/m²的rIL-2（0.03mg/m²的Proleukin rIL-2）。在每次rIL-2输注前，腹腔内注射1.5升5%葡萄糖0.25%生理盐水。在第1天和第4天，从4名患者中的每一位获取多个腹腔液样本，以检测IL-2、内源性细胞因子和可溶性IL-2受体（IL-2R-α）。腹腔液中的IL-2浓度通过生物测定法测定，干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α、IL-10、转化生长因子（TGF）-β2和sIL-2R-α通过酶联免疫吸附测定法测定。在第1天、第4天以及后续的停药日，用一组单克隆抗体染色后，测定每微升细胞数量和淋巴细胞亚群百分比。腹腔中IL-2的消失情况可用具有恒速输注和双指数处置的药代动力学模型很好地描述。约90%的IL-2消失发生在β期，在此期间IL-2浓度维持在约10 - 30ng/ml（第1天和第4天），第1天和第4天的中位t1/2β分别为21.5小时和9.2小时。在4名患者中的每一位，均在第1天和第4天观察到腹腔内IL-10的产生（最高387pg/ml）。在第4天观察到IFN-γ和sIL-2R-α的最高水平（IFN-γ 217pg/ml；sIL2-R-α：3486U/ml）。未观察到TNF-α或TGF-β2增加。观察到腹腔内CD3⁺、CD4⁺、CD8⁺、CD16⁺和CD56⁺细胞大幅增加。我们得出结论，以0.03mg/m²腹腔内给予rIL-2后，腹腔液中可产生具有生物活性水平的IL-2。
