Intracerebral chemotherapy in the 9L rat brain tumor model

Summary We have used the 9L rat brain tumor model to search for effective chemotherapeutic approaches to the management of brain tumors. Several antineoplastic agents which have been proposed or are currently being used for human brain tumors, including 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), bleomycin, aziridinylbenzoquinone (AZQ), cis-Platinum, and acivicin, were administered intravenously (iv), intraperitoneally (ip), or intracerebrally (ic) to rats burdened with the intracranial 9L gliosarcoma. The results confirm that BCNU is the most effective systemic agent among the chemotherapeutic agents tested as indicated by its ability to significantly increase the median survival time (MST) and life span of the tumor-burdened animals. Bleomycin is an effective agent against the intracranial 9L tumor when administered ic. While neither systemic single iv dose AZQ (0.5–2.5 mg/kg) nor multiple ip treatments (0.5–1.0 mg/kg × 5, q 6 h) were effective in prolonging the survival, single is dose AZQ (5–50 g/rat) treatment significantly increased the MST of the treated animals (P < 0.05). Systemic AZQ treatments using higher doses produced a hematological toxicity, resulting in a decrease in MST of the treated animals. Cis-Platinum, either administered ip or ic, produced only a marginal effect on survival, although acute neurologic toxicity limited the dose of cis-Patinum that could be administered ic. Acivicin, either administered ip or ic, produced no effect on the survival of treated animals. Our results suggest that local treatment with certain antineoplastic agents may be an efficient therapy in the management of brain tumors.     

Bleomycin therapy and Anaesthesia

Bleomycin is a cytotoxic drug used in the treatment of teratoma of the testis. This drug appears to sensitize the lungs so that acute lung damage occurs with concentrations of oxygen normally considered free from toxic effects. Two anaesthetics administered to the same patient undergoing thoracotomy are reported. No postoperative lung damage was produced on either occasion.     

In vitro tracheal hyperresponsiveness to muscarinic receptor stimulation by carbachol in a rat model of bleomycin-induced pulmonary fibrosis

1 Bleomycin-induced lung injury is widely used as an experimental model to investigate the pathophysiology of pulmonary fibrosis but the alterations in the pharmacological responsiveness of airways isolated from bleomycin-exposed animals has been scarcely investigated. The aim of this study was to examine the in vitro tracheal responses to muscarinic receptor stimulation with carbachol in a rat bleomycin model. 2 Concentration-response curves to carbachol (10 nm to 0.1 mm) were obtained in tracheal rings isolated from Sprague-Dawley rats 14 days after endotracheal bleomycin or saline. The intracellular calcium signal in response to carbachol (10 microm) was measured by epifluorescence microscopy using fura-2 in primary cultures of tracheal smooth muscle cells from bleomycin- and saline-exposed rats. Circulating plasma tumour necrosis factor (TNF)-alpha/interleukin (IL)-1beta levels were measured by enzyme-linked immunosorbent assay. 3 Maximal contraction in response to carbachol was significantly greater in tracheal rings from bleomycin-exposed rats compared with controls (15.8 +/- 1.3 mN vs. 11.8 +/- 1.4 mN; n = 19, P < 0.05). 4 Carbachol (10 microm) elicited a transient increase of intracellular calcium with greater increment in tracheal smooth muscle cells from bleomycin-exposed rats compared with controls (372 +/- 42 nmvs. 176 +/- 20 nm; n = 7, P < 0.01). 5 Circulating plasma levels of TNF-alpha/IL-1beta were augmented in bleomycin-exposed rats compared with controls. Tissue incubation with TNF-alpha (100 ng ml(-1))/IL-1beta (10 ng ml(-1)) increased in vitro tracheal responsiveness to carbachol. 6 In conclusion, tracheal contraction in response to muscarinic receptor stimulation with carbachol was increased in bleomycin-exposed rats. This in vitro cholinergic hyperresponsiveness may be related to the augmented levels of inflammatory cytokines in bleomycin-exposed rats.     

Intracavitary bleomycin for the control of malignant effusions

The results of treatment with intracavitary bleomycin are reported in twenty patients with a malignant pleural effusion and five patients with malignant ascites. The control rate was 17/20 (85%) patients with malignant pleural effusions and 3/5 (60%) patients with malignant ascites. Toxicities were minimal with fever being the most common side effect in four patients (16%. Bleomycin is an effective and nontoxic sclerosing agent.     

肺纤维化大鼠肺泡巨噬细胞细胞因子的研究

目的：研究肺泡巨噬细胞（ＡＭ）释放的细胞因子在肺纤维化中的作用。方法：采用７ＴＤ１细胞增殖反应测定法和微量滤膜法趋化实验，动态观察了博莱霉素（ＢＬＭ）肺纤维化大鼠ＡＭ释放白细胞介素－６（ＩＬ－６）及白细胞介素－８（ＩＬ－８）的变化。结果：①灌注后第１天，ＩＬ－６开始增加，于第２８天达高峰（Ｐ＜０．０１）。②灌注后第１天，ＩＬ－８即增高，第３天达高峰（Ｐ＜０．０１），第７天开始下降，逐渐降至对照组水平。结论：ＡＭ在ＢＬＭ致小鼠肺纤维化模型中被激活，并于体外自发释放ＩＬ－６及ＩＬ－８，提示细胞因子参与该模型中肺损伤及肺纤维化的发生与发展。     

静脉注射不同剂量博莱霉素诱导小鼠肺纤维化的比较研究

目的寻求建立小鼠肺纤维化模型的改良方案。方法雄性C57BL/6小鼠随机分为单次和多次注射模型组。单次注射模型组分为博莱霉素100、150、200 mg/kg组及对照组1;多次注射模型组分为博莱霉素50 mg/kg组及对照组2。取小鼠肺组织行病理检查,免疫组化检测肺Ⅰ型胶原蛋白、TGF-β1和α-SMA的表达。结果在单次注射模型组中,100、150、200 mg/kg组的肺泡炎均于第2周达峰(P0.01);肺纤维化分别在第2、4、4周达峰(P0.01)。在多次注射模型组中,50 mg/kg组肺泡炎和肺纤维化均在第10周达峰(P0.05)。TGF-β1和α-SMA在肺泡炎和纤维化部位表达明显增加。结论尾静脉单次注射博莱霉素200mg/kg可有效诱导肺纤维化,复制一个相对稳定的肺纤维化模型。     

帕夫林通过抑制NLRP3形成减轻博莱霉素诱导的小鼠肺纤维化

目的：探讨帕夫林（paeoniflorin,PA）对博莱霉素（bleomycin,BLM）诱导的小鼠肺纤维化的影响及其作用机制。方法：将60只SPF级雄性C57BL/6小鼠随机分为4组：对照组（sham operation,SH）、对照组+帕夫林组（SH+PA）、模型组（BLM）、模型组+帕夫林（BLM+PA）;气管内滴注博莱霉素（2 mg/kg）建立小鼠肺纤维化模型,对照组气管内滴注生理盐水,从造模当天开始,SH+PA、BLM+PA组小鼠每日给予50 mg/kg帕夫林灌胃,SH、BLM组小鼠每日给予等量生理盐水灌胃;在造模第14天处死小鼠,留取小鼠肺组织。记录各组小鼠体重变化;统计各组小鼠生存率;HE染色法观察小鼠肺组织纤维化程度;肺组织匀浆羟脯氨酸定量评估肺组织胶原蛋白含量;ELISA法测定肺组织匀浆中白介素（interleukin,IL）-18、IL-1β含量;Western blot法检测肺组织匀浆中NLRP3、转化生长因子β1（transforming growth factor-β1,TGF-β1）表达水平。结果：与对照组相比,帕夫林可显著提高小鼠生存率;经帕夫林治疗14 d后,小鼠肺组织纤维化病变较模型组减轻;小鼠肺组织胶原蛋白含量显著降低（P＜0.05）;小鼠外周血及肺组织中IL-18、IL-1β含量较模型组相比明显减少（P＜0.05）;与模型组相比,NLRP3蛋白水平以及TGF-β1蛋白表达水平显著下调（P＜0.05）。结论：帕夫林可减轻博莱霉素诱导的小鼠肺纤维化程度,其作用可能是通过抑制NLRP3炎症小体的形成发挥的。