IN-VIVO EFFICACY OF INTRATHECAL TRANSFERRIN-PSEUDOMONAS EXOTOXIN-A IMMUNOTOXIN AGAINST LOX-MELANOMA
IN-VIVO EFFICACY OF INTRATHECAL TRANSFERRIN-PSEUDOMONAS EXOTOXIN-A IMMUNOTOXIN AGAINST LOX-MELANOMA
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DOI：
10.1227/00006123-199404000-00012
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发表时间：
1994-04-01
期刊：
影响因子：
4.8
通讯作者：
FODSTAD, O
中科院分区：
文献类型：
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作者：
HALL, WA;MYKLEBUST, A;FODSTAD, O
由于全身癌症或原发中枢神经系统肿瘤通过脑脊液扩散而导致的肿瘤性脑膜炎预后非常差。目前对这种疾病的治疗是无效的，免疫毒素等新的治疗方式可能是有益的。为了验证转铁蛋白-假单胞菌外毒素A(TFN-PE)免疫毒素鞘内治疗的疗效，我们用LOX黑色素瘤来源的组织培养细胞在无瘤大鼠体内建立了人类癌性脑膜炎的动物模型。通过留置导管将5×10(5)LOX细胞注入鞘内，可在9.24±-1.77天内因胸髓和腰髓附近肿瘤生长的灶性沉积而导致可重复性的肢体截瘫。鞘内注射2.5或5杯的TFN-PE免疫毒素具有神经毒性，10只动物中有8只在24小时内死亡。中枢神经系统损伤的组织学证据被认为是中央管周围的出血性变性或颈髓水平的病理性裂隙。由于1杯鞘内注射TFN-PE免疫毒素未见神经毒性，因此在治疗实验中给予该剂量。鞘内注入LOX细胞24小时后，10只动物鞘内注射1杯TFN-PE或含0.1%人血清白蛋白的磷酸盐缓冲液(对照组)。与TFN-PE组相比，对照组动物在10.7d+/-2.75d出现截瘫，而TFN-PE组直到15.5d+/-4.58d才出现截瘫，截瘫开始时间平均延迟5d或31%(P=0.015)。在治疗人类肿瘤性脑膜炎的动物中观察到的截瘫发作的延迟支持了鞘内免疫毒素在全身或中枢神经系统癌症所致癌性脑膜炎患者的I/II期临床试验中的使用。
NEOPLASTIC MENINGITIS DUE to the dissemination of systemic cancer or primary central nervous system tumors through the cerebrospinal fluid carries a very poor prognosis. Current treatments for this disease are ineffective, and new therapeutic modalities such as immunotoxins may be beneficial. We created an animal model of human carcinomatous meningitis with LOX melanoma-derived tissue-culture cells in athymic rats for testing the efficacy of intrathecal therapy with transferrin-Pseudomonas exotoxin A (Tfn-PE) immunotoxin. An injection of 5 x 10(5) LOX cells into the intrathecal space through an indwelling catheter resulted in the reproducible development of lower-extremity paraplegia at 9.24 +/- 1.77 days because of focal deposits of tumor growth adjacent to the thoracic and lumbar spinal cord. A dose of 2.5 or 5 mug of intrathecal Tfn-PE immunotoxin was neurotoxic and resulted in the deaths of 8 of 10 animals within 24 hours. Histological evidence of central nervous system damage was seen as hemorrhagic degeneration around the central canal or a pathological cleft at the level of the cervical spinal cord. Because no neurotoxicity was seen with 1 mug of intrathecal Tfn-PE immunotoxin, this dose was administered in treatment experiments. Twenty-four hours after the intrathecal instillation of LOX cells, 10 animals received intrathecally either 1 mug of Tfn-PE or phosphate-buffered saline with 0.1% human serum albumin (control group). Control animals experienced lower-extremity paraplegia at 10.7 +/- 2.75 days compared with animals treated with Tfn-PE, which did not develop paralysis until 15.5 +/- 4.58 days, representing a mean delay in the onset of paraplegia of 5 days or 31% (P = 0.015). This observed delay in the onset of paraplegia in treated animals with human neoplastic meningitis supports the use of intrathecal immunotoxins for Phase I/II clinical trials in patients with carcinomatous meningitis from systemic or central nervous system cancer.