Da Pozzo L F, Hough K L, Holder W D
Department of Surgery, Stanford University School of Medicine, Calif.
Surgery. 1992 Mar;111(3):326-34.
A preclinical pilot study was done to evaluate the effects of a continuous regional hepatic arterial infusion of human recombinant interleukin-2 (IL-2) in dogs with an infusion pump. Preliminary studies demonstrated the ability to culture canine lymphokine-activated killer (LAK) cells in vitro and a canine LAK cell 15Cr assay was developed with a canine tumor cell line (CTAC) with appropriate controls. An in vitro study of the stability of IL-2 in the pump was done with a bioassay and enzyme-linked immunosorbent assay for IL-2 that demonstrated the stability of IL-2 during a 14-day period at 37 degrees C. Infusions of 300, 600, and 1200 units/kg/hr IL-2 were tested in vivo in dogs. LAK cell and natural killer cell activity, blood counts, and hepatic and renal function were monitored for 1 month. No significant natural killer or LAK response or toxicity was found at the 300 unit/kg/hr level. Infusion of 600 units/kg/hr was associated with a significant increase of the cytotoxic activity of peripheral blood lymphocytes after 3 weeks of treatment. At the 1200 unit/kg/hr level, increased activity occurred at 1 week and thereafter. The only significant toxicity was a 15% increase in body weight occurring during the infusion of 1200 units/kg/hr. Results of renal and hepatic function studies remained normal except for a slight elevation of transaminase levels after 4 weeks of 1200 units/kg/hr. A significant rise in eosinophil count was noted at each dosage level. Results of autopsies were unremarkable. These data demonstrate that continuous hepatic arterial regional infusion with relatively low doses of IL-2 is able to stimulate a sustained in vivo peripheral blood LAK cell effect in dogs with the absence of major side effects. These findings suggest that these methods may have both research application in large animals and clinical application in patients with tumors that are responsive to LAK cell lysis.
进行了一项临床前先导研究，以评估使用输液泵持续区域性肝动脉输注人重组白细胞介素-2（IL-2）对犬的影响。初步研究证明了体外培养犬淋巴因子激活的杀伤（LAK）细胞的能力，并开发了一种犬LAK细胞51Cr测定法，使用犬肿瘤细胞系（CTAC）并设置适当对照。用生物测定法和IL-2酶联免疫吸附测定法对泵中IL-2的稳定性进行了体外研究，结果表明IL-2在37℃下14天内保持稳定。在犬体内测试了300、600和1200单位/千克/小时IL-2的输注。对LAK细胞和自然杀伤细胞活性、血细胞计数以及肝肾功能进行了1个月的监测。在300单位/千克/小时水平未发现明显的自然杀伤或LAK反应及毒性。输注600单位/千克/小时与治疗3周后外周血淋巴细胞细胞毒性活性显著增加有关。在1200单位/千克/小时水平，1周后及之后活性增加。唯一显著的毒性是在输注1200单位/千克/小时期间体重增加15%。除了在1200单位/千克/小时输注4周后转氨酶水平略有升高外，肝肾功能研究结果仍正常。在每个剂量水平均观察到嗜酸性粒细胞计数显著升高。尸检结果无异常。这些数据表明，以相对低剂量的IL-2进行持续肝动脉区域输注能够在犬体内刺激持续的外周血LAK细胞效应，且无主要副作用。这些发现表明，这些方法可能在大型动物研究中有应用价值，并且在对LAK细胞溶解有反应的肿瘤患者中也有临床应用价值。
