The chemopotentiation of cisplatin by the novel bioreductive drug AQ4N

AQ4N is a bioreductive drug that can significantly enhance the anti-tumour effect of radiation and cyclophosphamide. The aim of this study was to examine the ability of AQ4N to potentiate the anti-tumour effect of cisplatin and to compare it to the chemopotentiation effect of tirapazamine. In the T50/80 murine tumour model, AQ4N (50-100 mg/kg) was administered 30 min, 2.5 or 6 h prior to cisplatin (4 mg/kg or 8 mg/kg); this produced an anti-tumour effect that was approximately 1.5 to 2 times greater than that achieved by a single 4 or 8 mg/kg dose of cisplatin. Tirapazamine (25 mg/kg) administered 2.5 h prior to cisplatin (4 mg/kg) resulted in a small increase in anti-tumour efficacy. AQ4N was also successful in enhancing the anti-tumour effect of cisplatin in the SCCVII and RIF-1 murine tumour models. This resulted in an increased cell kill of greater than 3 logs in both models; this was a greater cell kill than that observed for tirapazamine with cisplatin. Combination of cisplatin with AQ4N or tirapazamine resulted in no additional bone marrow toxicity compared to cisplatin administered alone. In conclusion, AQ4N has the potential to improve the clinical efficacy of cisplatin.     

Schedule-dependent response of neuroblastoma cell lines to combinations of etoposide and cisplatin

The growth inhibitory effects of cisplatin and etoposide on neuroblastoma cell lines were investigated in several scheduled combinations. Results were analyzed using median effect and combination index analyses. In all schedules in which cisplatin was administered prior to etoposide a synergistic effect was observed. Conversely, an antagonistic effect was seen in all schedules where etoposide was administered before cisplatin.     

环氧化酶-2抑制剂塞来昔布联合顺铂对A549人肺腺癌细胞株增殖影响的体外实验研究

目的观察环氧化酶-2（COX-2）抑制剂塞来昔布（Celecoxib）与化疗药物顺铂（DDP）联合应用对A549人肺腙癌细胞增殖的影响。方法应用MTS法检测Celecoxib与DDP联用对人肺腺癌A549细胞增殖的影响。结果在一定浓度范围内，Celecoxib和DDP均可抑制A549人肺腺癌细胞的生长，其抑制作用呈量-效关系。Celecoxib（0．35mg／L）与DDP联用可增强对A549细胞生长的抑制作用，DDP浓度≥1mg／L时两者具有协同或相加作用；且在一定浓度范围内，Celecoxib与DDP联用对细胞的生长抑制作用呈时-效关系。结论Celecoxib与DDP联合可增强对A549人肺腺癌细胞的生长抑制效应。     

Antitumor effect of JM-8 (a cisplatin analogue) on testicular cancer cells in vitro and in vivo

Using transplantable testicular tumor lines serially passaged in nude mice, the antitumor effect of JM-8, an analogue compound of cisplatin, was evaluated by clonogenic assay and in nude mice. JM-8 exhibited compatible tumor growth inhibition to that of 8 to 10 times the concentration of cisplatin both in vitro and in vivo. In addition, JM-8 had less toxicity than cisplatin in vivo. However, when JM-8 was adopted for treatment of regrowing tumors after repeated manipulations with cisplatin, it exerted less growth inhibition than cisplatin. Apart from this effect, it was considered that JM-8 could be substituted for cisplatin in clinical use.     

COX-2 抑制剂联合顺铂或X射线对A549肺腺癌细胞株的体外实验

 目的 观察环氧化酶-2（C0X-2）抑制剂塞来昔布（Celecoxib）联合化疗药物顺铂（DDP）或联合X射线对A549人肺腺癌细胞增殖的影响及可能机制。方法 应用MTS法分别检测Celecoxib与DDP联用对A549细胞增殖的影响及联合X射线对A549细胞存活分数（SF）的影响，流式细胞术检测细胞凋亡。结果 在一定浓度范围内，Celecoxib和DDP均可抑制A549人肺腺癌细胞的生长，其抑制作用呈量一效关系。两者联用可增强对A549细胞生长的抑制作用，DDP浓度≥1mg／L时两者具有协同或相加作用。Celecoxib与X射线联用可显著降低细胞存活分数（SF），增加细胞凋亡率。结论 Celecoxib与DDP联合可增强对A549人肺腺癌细胞的生长抑制效应；Celecoxib与X射线联合时，可增加AS49人肺腺癌细胞的凋亡率，增强其对放射的敏感性。     

白皮杉醇增强顺铂杀伤喉癌Hep-2细胞的作用及其机制

目的 探讨白皮杉醇增强顺铂对喉癌细胞的杀伤作用及其分子机制。方法 体外培养喉癌细胞Hep-2,联合使用白皮杉醇及顺铂,CCK8法检测喉癌Hep-2细胞的增殖能力,流式细胞术检测喉癌Hep-2细胞的凋亡率,Hoechst染色检测喉癌Hep-2细胞中细胞核固缩比例,蛋白印迹法检测BCL-2家族蛋白表达变化。结果 白皮杉醇在50 μmol/L时对喉癌Hep-2细胞的增殖凋亡并无显著影响。与顺铂组相比,白皮杉醇联合顺铂组细胞的增殖能力显著降低,48 h细胞吸光度值白皮杉醇联合顺铂组较顺铂组降低60%,流式细胞术检测发现48 h时,白皮杉醇联合顺铂组喉癌Hep-2细胞的凋亡率显著高于顺铂组（P<0.05）,Hoechst染色发现白皮杉醇联合顺铂组喉癌Hep-2细胞的细胞核固缩比例显著增高,差异有统计学意义。蛋白印迹检测发现,白皮杉醇可以显著下调BCL-2蛋白表达水平,上调BAX蛋白表达水平。结论 白皮杉醇可以有效增强顺铂对喉癌细胞的杀伤作用,其分子机制与白皮杉醇可以显著调控BCL-2家族蛋白表达有关。     

Combination of etoposide with cisplatin or cyclophosphamide in the treatment of mouse Lewis lung carcinoma

The effect of sequential combination of etoposide with cisplatin or cyclophosphamide on mouse Lewis lung carcinoma was investigated. Tumor cells were inoculated i.v. on day 0. Drugs were administered i.p. In combined treatment etoposide was consecutively administered once daily for 5 days on days 1 to 5 and 2 to 6 when cisplatin or cyclophosphamide were administered singly on days 6 and 1, respectively. In the combination of etoposide with cisplatin a highly synergistic effect was observed irrespective of the day of cisplatin administration. In the other combination with cyclophosphamide, a synergistic effect was similarly observed but the degree was much higher when cyclophosphamide was administered prior to etoposide administration.     

Antitumor effect of carboplatin and iproplatin on human urinary bladder and prostatic cancers grown in nude mice

Antitumor effects of carboplatin and iproplatin, a second-generation cisplatin analog were studied using cisplatin sensitive human urinary bladder (NM-B-1) and prostatic cancers (PRO-1) grown in nude mice. Both NM-B-1 and PRO-1 were sensitive to carboplatin and iproplatin. The tumor-regression effect of carboplatin at the fourfold dose of cisplatin was comparable to that of cisplatin. Iproplatin at the eight to sixteen times dose of cisplatin showed a comparable tumor regression to cisplatin. The range of effective dose was wider in carboplatin than cisplatin and that of iproplatin was not so wide as cisplatin.     

The effect of lonidamine alone and in combination with cisplatin on in vitro growth and viability of lung squamous cell carcinoma cell lines

Two non small cell lung cancer (NSCLC) cell lines were tested in vitro to evaluate the effect of lonidamine, cisplatin and combinations of these two agents using different doses and schedules. Lonidamine alone at concentrations greater than 50 micrograms/ml caused inhibition of cell growth in both monolayer and spheroid cell cultures. Cisplatin at concentrations of 10-20 microM caused a concentration dependent toxicity and inhibited growth in monolayer and spheroid cell cultures. Combination treatment of lonidamine and cisplatin caused concentration dependent effects. For 25 micrograms/ml lonidamine, there was no additive and in some cases an antagonistic effect when used with cisplatin. For higher lonidamine concentrations (75 and 100 micrograms ml), an additive effect with cisplatin (10-15 microM) was observed. This effect saturated for cisplatin concentrations of 20 microM. These data show some potential for lonidamine and cisplatin combination therapy but treatment doses and schedules will have to be identified so that the additive effect can be achieved at concentrations clinically attainable.     

Cisplatin and hyperthermia treatment of a C3H mammary carcinoma in vivo. Importance of sequence, interval, drug dose, and temperature.

The effect of combining cisplatin and hyperthermia was investigated in a C3H mammary carcinoma in vivo, using a regrowth delay assay. Cisplatin (6 mg/kg) was given i.p. at intervals ranging from 24 h before to 24 h after a 43.5 degrees C/60 min treatment. A supra-additive effect was obtained by giving cisplatin 15 min before heat, whereas an additive effect was obtained at all other intervals. The importance of cisplatin dose and heating temperature were investigated by giving variable cisplatin doses (2-8 mg/kg) 4 h or 15 min before a 60 min heating at temperatures in the range 40.5-43.5 degrees C. Linear relationships between length of regrowth delay and cisplatin dose were obtained both for cisplatin alone and for the combined treatment. The effect of the combined treatment could therefore be quantitated by a ratio (ER) between the slopes of dose-response curves. The ER values for cisplatin give 4 h before a 60 min heating at 42.5 or 43.5 degrees C were not significantly different from 1 (p greater than 0.5). In contrast, significant ER values were obtained above 40.5 degrees C (p less than 0.05) for cisplatin given 15 min before heat. The data demonstrates the possibility of achieving chemosensitization at clinically relevant temperatures.     

Effects of niosomal cisplatin and combination of the same with theophylline and with activated macrophages in murine B16F10 melanoma model

The use of cisplatin is limited due to its certain toxic effects. In the present study niosomes of cisplatin by using span 60 and cholesterol were prepared and investigated for antimetastatic activity in experimental metastatic model of B16F10 melanoma. Theophylline and its combination effect with free cisplatin and niosomal cisplatin were also carried out in the same model. The effect of treatment with activated macrophages alone and in combination with cisplatin, theophylline and niosomal cisplatin was also observed. Treatment with niosomal cisplatin (1 mg/kg) and combination of the same with theophylline (15 mg/kg) showed significant reduction in the number of lung nodules as compared to untreated control as well as with free cisplatin (1 mg/kg). The treatment with activated macrophages (activated by using Muramyl dipeptide) significantly reduced the secondary growth of tumor in lung. Niosomal cisplatin showed a significant protection against weight loss and bone marrow toxicity as compared to free cisplatin. These results suggest that cisplatin encapsulated in niosomes has significant antimetastatic activity and reduced toxicities than that of free cisplatin. However theophylline failed to show antimetastatic effect alone or in combination with cisplatin or with activated macrophages.     

术前新辅助化疗治疗局部晚期宫颈癌疗效观察

目的观察局部晚期宫颈癌术前新辅助化疗(NACT)中托泊替康联合顺铂与紫杉醇联合顺铂2种化疗方案的疗效及毒副反应。方法 55例术前局部晚期宫颈癌患者随机分为2组,治疗组29例术前接受托泊替康联合顺铂化疗,对照组26例术前接受紫杉醇联合顺铂化疗,比较观察2组的疗效和毒副反应。结果治疗组与对照组有效率分别为85.71%、88.46%,差异无统计学意义(P>0.05);对照组脱发较治疗组明显,差异有统计学意义(P<0.05)。结论术前NACT治疗局部晚期宫颈癌,托泊替康联合顺铂具有疗效好、毒副反应轻等优势。     

Enhancement of antineoplastic effects of cisplatin by a calmodulin antagonist (W-7) in nude mice bearing human ovarian carcinoma

The present study was designed to potentiate antineoplastic effects of cisplatin by combination with a calmodulin antagonist (W-7) using nude mice bearing human ovarian carcinoma. Tumor growth in nude mice treated with W-7 after (but not before) administration of cisplatin was significantly inhibited. Although treatment with cisplatin alone markedly inhibited lytic activity of the spleen cells in tumor-bearing nude mice against the tumor cells, the inhibitory effect was eliminated by subsequent treatment with W-7. There was no significant difference in the survival time between untreated and cisplatin-treated groups. Only when cisplatin was followed by W-7 was a significant enhancement by W-7 of the antitumor effect of cisplatin observed with respect to inhibition of the tumor growth as well as prolongation of the survival time.     

顺铂或多西紫杉醇同期放化疗治疗局部晚期宫颈癌疗效分析

目的：比较顺铂或多西紫杉醇同期放化疗治疗局部晚期宫颈癌疗效。方法：38例IIb到IVa期患者随机分为每周顺铂同期放化疗组（22例）或多西紫杉醇同期放化疗组（16例）。顺铂30mg/m2或多西紫杉醇25mg/m2抗过敏预处理,每周放疗的第一天同步静脉滴注,连续6周;放疗方法：两组患者外照射放疗采用直线加速器盆腔大野DT 30Gy后中央挡铅改为盆腔四野加量照射至DT 50Gy,常规分割,180-200cGy/F,盆腔四野照射期间每周局部后装铱192照射一次,每次剂量6Gy,共6次,A点剂量达3600cGy。观察两组治疗效果和不良反应并进行比较。结果：两组患者总有效率82%vs 87%,临床获益率91%vs 94%,差异无统计学意义（P〉0.05）;两组随访1年无进展生存率（PFS）比较77%vs 81%,总生存率（OS）95%vs 100%,差异无统计学意义（P〉0.05）;但多西紫杉醇同期放化组较顺铂同期放化组治疗无论在血液系统不良反应和非血液系统不良反应方面都明显降低,统计学比较差异有显著性P〈0.05。结论：多西紫杉醇同期放化疗可取得不亚于顺铂同期放化治疗的疗效,且多西紫杉醇不良反应明显降低。     

参归丸对顺铂化疗H22荷瘤小鼠的减毒增效作用及其机制

探讨参归丸的抑瘤作用及对顺铂化疗H22荷瘤小鼠的增效减毒作用。方法 建立小鼠H22肝癌移植瘤模型,随机分为模型组、顺铂组、参归丸组、参归丸加顺铂联合组,另设正常对照组。观察各组小鼠一般状况,计算有效体重变化;检测各给药组的抑瘤率、q值、肿瘤指数、肝脏、脾脏、胸腺、肾脏的器官指数。血常规检测白细胞计数,ELISA检测血清低氧诱导因子（HIF1α）的浓度,血生化检测乳酸脱氢酶（LDH）活力。结果 参归丸组和联合组的一般状况优于模型组和顺铂组;各治疗组的瘤体质量皆小于模型组的瘤体质量( P＜0.05),联合组的抑瘤率高于单用参归丸或顺铂组的抑瘤率,联合用药疗效具有相加效应;参归丸组有效体重增加、脾脏和胸腺指数高于顺铂组(P＜0.05);参归丸组和联合组血清HIF1α浓度低于模型组( P＜0.05);顺铂组血清LDH活性高于其他治疗组( P＜0.05)。结论 参归丸具有抑瘤作用和对顺铂化疗的增效减毒作用,其机制可能在一定程度上与降低小鼠血清中HIF1α浓度和LDH活性有关。     

吉非替尼联合顺铂对肺癌细胞增殖的协同抑制作用

目的：观察表皮生长因子受体酪氨酸激酶抑制剂吉非替尼（Gefitinib,G）与顺铂（Cisplatin,DDP）联合对肺癌细胞株A549增殖抑制的协同效应。方法：采用四甲基偶氮唑蓝（MTT）法检测不同浓度吉非替尼单药、顺铂单药以及两药联用对肺癌细胞株A549的抑制程度,并应用两药相互作用指数评价药物的联合效应。结果：在药物作用时间足够时,两药联用相对单药组能显著地提高肿瘤细胞的抑制率,并且抑制效率随药物浓度的增加而提高。当作用时间≥48h时,联用组A值相对于单药组明显降低（P〈0．05）。联用对肿瘤细胞增长的抑制作用在48h时较24h明显增高（P〈0．05）,并随着时间的延长呈现递增趋势,至72h后逐渐进入平台期（P〉0．05）。两药协同效应在作用24h时表现不明显,在48h后才开始出现（CDI〈1）。结论：在药物作用时间足够时,吉非替尼与顺铂联用对肺癌细胞的增殖具有协同抑制效应,可为临床应用提供参考。     

Histological response of cisplatin predicts patients' survival in oesophageal cancer and p53 protein accumulation in pretreatment biopsy is associated with cisplatin sensitivity

The aim of this study was to evaluate whether cisplatin sensitivity relates to patient's prognosis in oesophageal squamous cell carcinoma and to find a useful chemosensitivity molecular marker. 59 oesophageal squamous cell carcinoma (SCC) patients received cisplatin 30 mg/m2/week treatment of two to five cycles, followed by oesophagectomy. We analysed retrospectively whether the histological effect was related to patient's prognosis. Furthermore, to evaluate the relationship between the effect of preoperative cisplatin treatment and p53 and cyclin D1 expression, we investigated p53 and cyclin D1 expression in pretreatment biopsy samples using an immunohistochemical analysis and compared the results with the histological effect to cisplatin in the resected oesophagus. The cases that showed immunohistochemical p53 staining in the pretreatment biopsy samples were resistant to cisplatin (P = 0.032). However, there was no relationship between cyclin D1 expression and histological effect (P = 0.230). Nevertheless, combined analysis of p53 and cyclin D1 can predict histological effect (P = 0.032). The prognosis of cisplatin-sensitive cases was significantly better than that of cisplatin-resistant cases (P = 0.041). Cox's multivariate analysis revealed that the histological effect was an independent prognostic factor. In contrast, p53 protein accumulation and cyclin D1 were not. Histological response after neoadjuvant cisplatin treatment is a prognostic factor for oesophageal SCC and cisplatin chemotherapy may be selected according to the findings of p53 and cyclin D1 expression.     

Thermochemotherapy with cisplatin or carboplatin in the BT4 rat glioma in vitro and in vivo.

The effect of thermochemotherapy with cisplatin or carboplatin was compared in the BT4-cell line. In vitro: BT4C-cells were treated with different concentrations of cisplatin or carboplatin, with or without simultaneous hyperthermia. In vivo: Inbred BD IX rats with transplanted glioma-like BT4A or glioblastoma-like BT4An tumors on the hind leg were treated with cisplatin (4 mg/kg) or carboplatin (50 mg/kg), with or without local hyperthermia. In vitro the benefit of adding hyperthermia to chemotherapy was similar for cisplatin and carboplatin. For both cisplatin and carboplatin, the difference of treatment effect between thermochemotherapy and chemotherapy alone increased with higher drug concentrations. In vivo hyperthermia clearly enhanced the effect of carboplatin on BT4A tumors. When treating BT4An tumors, thermochemotherapy with cisplatin or carboplatin was equally effective. Both combinations were superior to treatment with hyperthermia alone. Local toxicity and weight loss following thermochemotherapy were comparable when substituting cisplatin with carboplatin.     

紫杉醇联合氟尿嘧啶和顺铂治疗晚期胃癌疗效观察

目的观察紫杉醇联合氟尿嘧啶、顺铂治疗晚期胃癌的临床疗效及毒副反应。方法 51例晚期胃癌患者随机以紫杉醇联合氟尿嘧啶、顺铂的方案或表柔比星联合氟尿嘧啶、顺铂的方案化疗,均化疗2个周期以上。每个周期28 d。结果紫杉醇联合氟尿嘧啶、顺铂方案的有效率（CR＋PR）为51.9%,毒副反应有神经毒性、脱发、关节肌肉疼痛及血液学毒性,胃肠道反应发生率为51.8%。表柔比星联合氟尿嘧啶、顺铂方案的有效率（CR＋PR）为50.0%,有脱发、心肌毒性、血液学毒性,胃肠道反应发生率为87.5%。结论紫杉醇联合氟尿嘧啶、顺铂治疗晚期胃癌与表柔比星联合氟尿嘧啶、顺铂治疗晚期胃癌相比,副反应均可耐受,但胃肠道反应相对较轻,疗效相当。