Mikami T, Uozumi T, Kurisu K, Kawamoto K, Kiya K, Hotta T
Department of Neurosurgery, Hiroshima University School of Medicine, Japan.
Biotherapy. 1994;8(1):7-17. doi: 10.1007/BF01878116.
The authors investigated the antitumor activities of rHuLT alone and in combination with etoposide on human meduloblastoma xenografts growing subcutaneously in nude mice. Intravenous administration of rHuLT (1.0 x 10(5) U/kg, 5.0 x 10(5)U/kg, 2.5 x 10(6)U/kg, three times a week for three weeks) suppressed medulloblastoma growth depending on the dose. However, the highest dosage caused serious side effects. Combining rHuLT (intravenously, 5.0 x 10(5)U/kg, three times a week for three weeks) with etoposide (intraperitoneally, 20mg/kg, once a week for three weeks) increased the antitumor activity without causing serious toxicity. Microscopically, tumor specimen showed thrombosed tumor vessels and massive necrosis 3 weeks after rHuLT treatment. Ultrastructural examination revealed that 120 minutes after the administration of rHuLT alone, disruption of interendothelial junctions was evident, and that the endothelial cells were destroyed at 240 minutes. Concentration of etoposide in tumor tissue peaked 30 minutes after intraperitoneal administration, and then decreased with time. When etoposide was administered in combination with rHuLT, the concentration of etoposide in tumor tissue after 60 to 240 minutes was significantly higher than when etoposide was given alone, and the area under the concentration versus time curve was also greater for the tumors of mice with combination treatment. The findings suggest that the proper combination of rHuLT and etoposide may have synergistic antitumor activities. Histological changes suggest that increased concentrations of etoposide within the tumor after combination therapy may occur due to increased vascular permeability and/or decreased etoposide clearance which is the result of blood statis in the tumor vasculature.
作者研究了重组人白细胞介素-2（rHuLT）单独及与依托泊苷联合对裸鼠皮下生长的人髓母细胞瘤异种移植物的抗肿瘤活性。静脉注射rHuLT（1.0×10⁵U/kg、5.0×10⁵U/kg、2.5×10⁶U/kg，每周3次，共3周）可抑制髓母细胞瘤生长，且呈剂量依赖性。然而，最高剂量会引起严重的副作用。将rHuLT（静脉注射，5.0×10⁵U/kg，每周3次，共3周）与依托泊苷（腹腔注射，20mg/kg，每周1次，共3周）联合使用，可增强抗肿瘤活性且不会引起严重毒性。显微镜检查显示，rHuLT治疗3周后，肿瘤标本出现血栓形成的肿瘤血管和大片坏死。超微结构检查显示，单独注射rHuLT 120分钟后，内皮细胞间连接明显破坏，240分钟时内皮细胞被破坏。腹腔注射后30分钟，肿瘤组织中依托泊苷浓度达到峰值，随后随时间下降。当依托泊苷与rHuLT联合使用时，60至240分钟后肿瘤组织中依托泊苷浓度显著高于单独使用依托泊苷时，联合治疗小鼠肿瘤的浓度-时间曲线下面积也更大。这些发现表明，rHuLT与依托泊苷的适当联合可能具有协同抗肿瘤活性。组织学变化表明，联合治疗后肿瘤内依托泊苷浓度增加可能是由于血管通透性增加和/或依托泊苷清除率降低所致，而后者是肿瘤血管内血液淤滞的结果。
