Amifostine: potential for clinically useful cytoprotection

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radio-protectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclophosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on non-hematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994     

重组人硫氧还蛋白抗柯萨奇B3m病毒损伤的研究

目的 观察重组人硫氧还蛋白(TRX)对柯萨奇B3m病毒(CVB3m)致HeLa细胞损伤的保护作用,并检测TRX对病毒复制的抑制作用.方法 采用IOTCID50的CVB3m病毒感染HeLa细胞,给予不同剂量的TRX(2、5、10mg/L)加以保护,实验设TRX保护组、病毒感染组、TRX对照组和对照组,每组设6个复孔.采用四甲基偶氮唑盐(MTT)和相差显微镜观察细胞生长情况.结果 相差显微镜下对照组HeLa细胞排列紧密、呈多角形;病毒感染组HeLa细胞排列不紧密,细胞明显变网、脱落;TRX保护组(2、5、10 mg/L)随TRX剂量增加HeLa细胞形态明显改善.MTT结果显示,TRX对照组(2、5、10 mg/L)生长抑制率(1.2%、2.9%、6.3%)与对照组(0)比较,差异无统计学意义(P均>0.05);TRX保护组(2、5、10 mg/L)生长抑制率(32.0%、28.0%、27.0%)与病毒感染组(51.7%)比较,均有降低(P均<0.05).病毒复制抑制作用结果显示,TRX保护组(2、5、10 mg/L)生长抑制率(26.0%、27.0%、10.9%)与病毒感染组(60.0%)比较,均有降低(P均<0.05);TRX各保护组之间比较,低剂量组(2、5 mg/L)与高剂量组(10 mg/L)间差异有统计学意义(P均<0.05).结论 重组人TRX(2、5、10mg/L)可以减轻CVB3m病毒导致的HeLa细胞损伤,对细胞无明显毒性作用,并具有抑制病毒复制的作用.     

硫化氢对PC12细胞存活素表达的影响及其神经保护作用

目的 探讨硫化氢(H2s)对PC12细胞存活素表达的影响及其神经保护作用.方法 应用Western blot检测不同浓度(50～800 μmol/L)的H2S供体硫氢化钠(NaHS)处理PC12细胞不同时间(0～180min)诱导PC12细胞存活素表达的量效和时效关系;细胞计数Kit-8(CCK-8)比色法检测细胞的存活率.结果应用不同浓度NaHS处理PC12细胞30 min后.在50～200 μmol/L浓度范围内呈浓度依赖性地促进存活素表达:但随着NaHS浓度的增加,存活素表达逐渐下降,当NaHS 浓度达800 μmol/L时存活素表达低于正常.应用400 μmo/L NariS处理PC12细胞不同时间,在0～60min时间范围内呈时间依赖性地促进PC12细胞存活素的表达,但随着处理时间的继续延长,存活索的表达逐渐下降.另一方面.400 μmo/L NariS预处理还能增强氯化钴(COCl2)对存活素表达的促进作用.并可显著减轻CoCl2对PC12细胞的损伤作用,使细胞存活率增加.结论 在一定浓度和时间范围内H2S可上调存活素的表达,此作用可能与其保护PC12细胞对抗化学性缺氧损伤有关.     

Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K/Akt/Nrf2-dependent pathway in human dopaminergic cells

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a popular traditional herbal medicine. Ginsenoside Rb1 (Rb1), an active component commonly found in ginseng root, is a phytoestrogen that exerts estrogen-like activity. In this study, we demonstrate that the phytoestrogen Rb1 inhibits 6-hydroxydopamine (6-OHDA)-induced oxidative injury via an ER-dependent Gβ1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of SH-SY5Y cells with Rb1 significantly reduced 6-OHDA-induced caspase-3 activation and subsequent cell death. Rb1 also up-regulated HO-1 expression, which conferred cytoprotection against 6-OHDA-induced oxidative injury. Moreover, Rb1 induced both Nrf2 nuclear translocation, which is upstream of HO-1 expression and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Also, Rb1-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that Rb1 augments the cellular antioxidant defenses through ER-dependent HO-1 induction via the Gβ1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress. Thus our study indicates that Rb1 has a partial cytoprotective role in dopaminergic cell culture systems.     

促红细胞生成素的临床应用进展

了解促红细胞生成素（Erythropoietin,EPO）在临床实践中的应用现状,探索和开发其在临床实践中的新使用途径。通过检索国内外最近几年有关EPO临床应用的文献报道得知,随着人们对EPO研究的不断深入,发现它具有促红细胞生成、抗炎症反应、抗细胞凋亡、保护细胞、增强免疫功能等许多种生物学功能,并引起了人们对它极大的研究兴趣。EPO作为一种多效能细胞因子,在众多系统及器官中均有作用靶点,这将为EPO在临床具有潜在的广泛的应用前景提供理论依据。     

Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: report of a randomized comparative trial

PURPOSE: To determine the ability of amifostine to reduce the severity and/or incidence of the acute toxicities of concurrent chemotherapy and radiotherapy (RT) for non-small-cell lung cancer. METHODS AND MATERIALS: Patients with inoperable, nonmetastatic non-small-cell lung cancer receiving concurrent chemoradiotherapy were randomized to one of two treatment groups. Arm 1 patients received thoracic RT (total dose, 69.6 Gy in 58 fractions of 1.2 Gy b.i.d. 5 d/wk), plus oral etoposide (50 mg b.i.d. 30 min before thoracic RT for 10 days, repeated on Day 29) and cisplatin (50 mg/m2 i.v. on Days 1, 8, 29, and 36). Arm 2 patients received the same treatment plus amifostine (500 mg i.v. 20-30 min before any treatment the first 2 days of each week). Acute effects were assessed using the National Cancer Institute Common Toxicity Criteria. RESULTS: Sixty-two patients were enrolled between November 1998 and January 2001. The minimal follow-up was 24 months, and the median follow-up of living patients was 31 months. The patient and tumor characteristics were equally distributed between the patients in the two arms. The median survival time was 20 months in Arm 1 patients and 19 months in Arm 2 patients. The maximal esophageal toxicity was mild (Grade 1) in 23%, moderate (Grade 2) in 42%, and severe (Grade 3-4) in 35% of patients in Arm 1; the corresponding rates for the Arm 2 patients were 48%, 35%, and 16% (p = 0.021). Severe pneumonitis occurred in 16% of the Arm 1 and none of the Arm 2 patients (p = 0.020, chi-square test). Neutropenic fever occurred in 39% of Arm 1 and 16% of Arm 2 patients (p = 0.046, chi-square test). Mild hypotension, dysgeusia, and sneezing were significantly more frequent among the patients in Arm 2. CONCLUSION: Amifostine reduced the severity and incidence of acute esophageal, pulmonary, and hematologic toxicity resulting from concurrent cisplatin-based chemotherapy and RT. Amifostine had no apparent effect on survival in these patients with unresectable non-small-cell lung cancer, suggesting that it does not have a tumor-protective effect.     

生姜提取物对X射线致小鼠红细胞损伤的保护作用

目的观察生姜提取物对X射线致小鼠外周血细胞损伤的保护作用.方法选择昆明种小鼠100只,随机分为5组(1个未照射组,1个单纯照射组,3个生姜提取物暴露组),雌雄各半,3个生姜提取物暴露组分别在照射前给予不同剂量生姜提取物(9.3、4.7、2.3 ml/kg)灌胃,非照射组和单纯照射组分别以相同体积的玉米油灌胃.X射线照射的剂量为2 Gy,照射2次,间隔24 h,末次照射后48 h,分别测定血中红细胞计数(RBC)、血红蛋白含量(HCB)、红细胞比积(HCT)、红细胞平均体积(MCV)、红细胞平均血红蛋白浓度(MCHC)、红细胞平均血红蛋白量(MCH)、红细胞体积分布宽度(RDW).结果与未照射组比较,单纯照射组X射线暴露可引起雌、雄小鼠RBC、HCB、HCT减少,MCH、RDW增高,还可导致雌性小鼠MCHC的增高(P＜0.05).而与单纯照射组比较,4.7、2.3 ml/kg生姜提取物组雌、雄小鼠RBC、HCB、HCT上升,RDW下降,,雌性小鼠MCH下降(P＜0.05).结论生姜提取物对X射线引起的小鼠RBC损伤具有保护作用.     

HSP70基因转染对人心肌细胞的保护作用

目的探讨利用热休克蛋白70(HSP70)基因转染技术保护人心肌细胞的可行性。方法用指质体介导的基因转移技术,研究了外源性HSP70基因高表达对人心肌细胞的保护作用。结果转染的心肌细胞在正常温度(37℃)下,可高水平表达HSP70,模拟缺血实验后,心肌肌酸激酶(CK-MB)释放量为(159.5±24.1)IU／L几,细胞生存率为(33.78±5.4)％,其抗模拟缺血能力明显高于对照组,而与热休克预处理后24小时组无显著差异。结论基因转染造成的HSP70高表达可保护人心肌细胞。     

Gastric antisecretory and antiulcer activities of Cyclea peltata (Lam.) Hook. f. & Thoms. in rats

Ethnopharmacological relevance

Cyclea peltata (Lam.) Hook. f. &; Thoms. (Menispermaceae), locally called ‘Padathaali/Padakizhangu’ is used in Ayurvedic medicine to treat peptic ulcer.

Aim of the study

To evaluate the gastric antisecretory and antiulcer activity of Cyclea peltata.

Materials and methods

The ethanolic extract of Cyclea peltata root was used to evaluate its gastric antisecretory and antiulcer effect in the pylorus-ligated rat model and gastric lesions induced by ethanol or ethanol and indomethacin respectively in rats. The levels of gastric wall mucus, non-protein sulfhydryl groups (NP-SH), malondialdehyde, protein and catalase activity in the stomach samples of Cyclea peltata treated and control groups of rats were also quantified.

Results

The ethanolic extract of Cyclea peltata roots showed significant antisecretory activity as evidenced by decreased pepsin secretion, gastric juice volume and acid output in pylorus-ligated rats. Pretreatment with Cyclea peltata extract provided significant protection against the peptic ulceration caused by ethanol administered individually, or in combination with indomethacin. Our studies also revealed that pretreatment with Cyclea peltata significantly increased the gastric protein and catalase concentration of ethanol treated rats. Further, it showed significant gastroprotective effects on the stomach wall of ethanol or ethanol and indomethacin treated rats by decreasing malondialdehyde level, increasing the gastric wall mucus and non-protein sulfhydryl groups.

Conclusion

The present findings demonstrate that Cyclea peltata ethanolic extract has potent antisecretory and antiulcer effects and justify the traditional/ethnic usage of this herb to treat peptic ulcers and consequent stomach ache.     

甘氨酸对脑死亡大鼠供肝损伤的防护作用

目的探讨甘氨酸对脑死亡大鼠供肝损伤的防护作用。方法雄性Wistar大鼠42只,随机分为3组B组为脑死亡大鼠供肝移植组,G组为甘氨酸防护组,S组为士的宁拮抗组。3个组的供者均为脑死亡大鼠,在供者脑死亡模型建立后、供肝冷灌洗时和移植肝门静脉血流恢复时,G组分别给予0.6mmol、25μmol和25μmol的甘氨酸,S组除给予和G组同剂量的甘氨酸外,并给予士的宁(甘氨酸和士的宁浓度比为1000∶1),B组不作处理。测定供肝冷灌洗前、移植肝门静脉血流恢复后2h和6h时下腔静脉血中丙氨酸转氨酶、天冬氨酸转氨酶、透明质酸和肿瘤坏死因子α的水平,电镜观察移植肝门静脉血流恢复后6h的肝脏形态变化,原位末端标记法检测肝脏细胞凋亡情况。结果3个组除移植肝门静脉血流恢复后2h的透明质酸水平的差异无显著性外,其它指标在3个采血时间点的水平,G组均显著低于B组和S组(P<0.01),而B、S组间各项指标的差异无显著性;G组移植肝门静脉血流恢复6h的肝组织损伤明显轻于B、S组,Kupffer细胞的活化也不显著。结论甘氨酸能明显减轻脑死亡大鼠供肝的损伤。