Watts R G, Merchant R E
Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Neurosurgery. 1992 Jul;31(1):89-98; discussion 98-9. doi: 10.1227/00006123-199207000-00013.
It is well documented that drug delivery into experimental and human brain tumors is limited by the variably intact blood-brain barrier (BBB) at the growing edge. The aim of the present investigation was to examine the histopathological changes that occur after a single intralesional injection of human recombinant interleukin-2 (rIL-2) into a growing glioma and determine whether the injection improved delivery of cytotoxic drug into the neuropil surrounding the site of lymphokine injection. Because an intracerebral injection of rIL-2 causes a temporary breakdown in the BBB, we hoped to enhance drug penetration into peritumoral areas of brain with an intact BBB by using the novel biomodulating effect of rIL-2 on the cerebral endothelial cells. The results demonstrated that an intralesional injection of 7.2 x 10(4) National Units rIL-2 on Day 7 after tumor inoculation did not accentuate the already increased cerebrovascular permeability produced by the glioma nor did rIL-2 trigger additional or aggravate neurological deficits in glioma-bearing rats. Before the administration of chemotherapy in vivo, the RT-2 glioma cells were tested for in vitro sensitivity by colorimetric assay. At 24 hours after exposure to either methotrexate (MTX), vincristine (VIN), or doxorubicin (DOX), no significant inhibition of metabolic activity was observed. In contrast, a timed pulsed of any drug for 5 minutes caused significant dose-dependent inhibition of RT-2 glioma cells at 48 hours to 5 days after drug administration. Animal models receiving an intralesional injection of rIL-2 followed 3 days later by an intravenous dose of 30 mg/kg MTX, 0.23 mg/kg VIN, or 10 mg/kg DOX demonstrated that only MTX combined with intralesional rIL-2 significantly inhibited intracranial proliferation of RT-2 glioma cells. Use of intralesional rIL-2 and intravenous chemotherapy, however, did not significantly increase survival in this animal model of glioma. These results show that the combination of cytotoxic drugs with intralesional rIL-2 can be safely applied in the management of glioma and may form a rational basis for additional pharmacological investigations of a wider assortment of chemotherapies in combination with rIL-2 for intracranial malignancies.
有充分的文献记载，向实验性和人类脑肿瘤的药物递送受到生长边缘处可变完整的血脑屏障（BBB）的限制。本研究的目的是检查在生长中的胶质瘤内单次瘤内注射人重组白细胞介素-2（rIL-2）后发生的组织病理学变化，并确定该注射是否改善了细胞毒性药物向淋巴因子注射部位周围神经纤维网的递送。由于脑内注射rIL-2会导致血脑屏障暂时破坏，我们希望通过利用rIL-2对脑内皮细胞的新型生物调节作用来增强药物向具有完整血脑屏障的脑肿瘤周围区域的渗透。结果表明，在肿瘤接种后第7天瘤内注射7.2×10⁴国际单位的rIL-2，既没有加剧胶质瘤已经导致的脑血管通透性增加，rIL-2也没有引发或加重荷瘤大鼠的神经功能缺损。在体内进行化疗之前，通过比色法检测RT-2胶质瘤细胞的体外敏感性。在暴露于甲氨蝶呤（MTX）、长春新碱（VIN）或阿霉素（DOX）24小时后，未观察到代谢活性的显著抑制。相反，在给药后48小时至5天，任何一种药物进行5分钟的定时脉冲给药均导致对RT-2胶质瘤细胞的显著剂量依赖性抑制。接受瘤内注射rIL-2，3天后静脉注射30mg/kg MTX、0.23mg/kg VIN或10mg/kg DOX的动物模型表明，只有MTX与瘤内rIL-2联合使用能显著抑制RT-2胶质瘤细胞的颅内增殖。然而，在这个胶质瘤动物模型中，使用瘤内rIL-2和静脉化疗并没有显著提高生存率。这些结果表明，细胞毒性药物与瘤内rIL-2联合应用可安全用于胶质瘤的治疗，并可能为进一步开展更广泛的化疗药物与rIL-2联合治疗颅内恶性肿瘤的药理学研究提供合理依据。
