Chemotherapy of experimental meningeal carcinomatosis.
Chemotherapy of experimental meningeal carcinomatosis.
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实验性脑膜癌病的化疗。
作者：
Y. Ushio;J. Posner;W. Shapiro
用成年雌性Wistar大鼠脑池内接种1×106 Walker 256癌肉瘤细胞进行实验性脑膜癌病的化疗研究。未经治疗的动物出现脑膜肿瘤浸润，导致13至15天内死亡。肿瘤生长堵塞蛛网膜下腔脑脊液通路，侵入脑、脊髓和神经根，并产生脑积水。
单次静脉注射化疗。尝试在肿瘤接种后第5天、第8天或第11天给药。环磷酰胺100 mg/kg可使大鼠的中位存活时间增加500%以上，治愈率高达60%。1-(2-氯乙基)-3-环己基-1-亚硝脲30 mg/kg，中位存活时间提高700%以上，治愈率达70%以上。1-(2-氯乙基)-3-(反式-4-甲基环己基)-1-亚硝脲，30 mg/kg，中位存活时间增加最多，达241%。静脉注射甲氨蝶呤100 mg/kg可使小鼠的中位存活时间最大增加69%，而脑室注射甲氨蝶呤1~10 mg/kg可使存活时间增加24%。甲氨蝶呤1 mg/kg分4次脑室给药，可使小鼠存活时间增加100%。脑室内或静脉注射。1-β-d-阿拉伯呋喃糖胞嘧啶无效。
结果证实了容易通过血脑屏障的药物(亚硝脲)的治疗价值，以及那些不能通过的药物(甲氨蝶呤)需要脑室注射。令人惊讶的是，一种被认为不会越过屏障的药物--环磷酰胺--非常有效，而且静脉注射的剂量很高。甲氨蝶呤的效果很小，这表明肿瘤生长绕过了血脑屏障，可能是通过新生血管。这些结果表明，有必要对人类脑膜癌病进行系统治疗。
Chemotherapy of experimental meningeal carcinomatosis was studied in adult female Wistar rats inoculated intracisternally with 1 × 106 Walker 256 carcinosarcoma cells. Nontreated animals developed meningeal tumor infiltration, which caused death in 13 to 15 days. Tumor growth blocked the subarachnoid cerebrospinal fluid pathways; infiltrated the brain, spinal cord, and nerve roots; and produced hydrocephalus.
Chemotherapy, by a single i.v. dose on Day 5, 8, or 11 after tumor inoculation, was attempted. Cyclophosphamide, 100 mg/kg, increased median survival time more than 500% and cured up to 60% of the rats. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, 30 mg/kg, increased median survival time over 700%, curing 70%. 1-(2-Chloroethyl)-3-( trans -4-methylcyclohexyl)-1-nitrosourea, 30 mg/kg, produced a maximal increased median survival time of 241%. Methotrexate, 100 mg/kg i.v., yielded a maximal increase in median survival time of 69%, while intraventricular methotrexate in doses of 1 to 10 mg/kg increased survival time by 24%. Methotrexate, 1 mg/kg by intraventricular infusion in 4 doses, increased survival time 100%. Intraventricular or i.v. 1-β-d-arabinofuranosylcytosine was ineffective.
The results confirmed the therapeutic value of drugs that easily cross the blood-brain barrier (the nitrosoureas) and the requirement for intraventricular injection for those that do not cross (methotrexate). Surprisingly, a drug thought not to cross the barrier, cyclophosphamide, was very effective, and high-dose i.v. methotrexate was minimally effective, suggesting that tumor growth circumvents the blood-brain barrier, probably by neovascularization. These results imply the need to examine systemic therapy for human meningeal carcinomatosis.