Synergism between alkylating agent and cis-platin with moderate local hyperthermia: the effect of multidrug chemotherapy in an animal system

The combined effect of multidrug chemotherapy given in combination with hyperthermia was investigated using early-generation isotransplants of a spontaneous fibrosarcoma, FSa-II in C3Hf/Sed mice. Combinations of various types of chemotherapeutic agents, including alkylating agents, cyclophosphamide (CY) and 1, 3-bis(2-chloroethyl)-1-nitro-sourea (BCNU); antibiotics, bleomycin (BLM) and mitomycin C (MMC); an antimetabolite, 5-fluorouracil (5FU); and a platinum complex, cis-diamminedichloro-platinum(II) (cDDP), were examined using the tumour growth (TG) time assay. Simultaneously, the effect of glucose on the response to thermochemotherapy was investigated. Graded doses of the multidrugs were given i.p. immediately before hyperthermia with or without a glucose dose of 5 g/kg given i.p. 60 min before hyperthermia. Hyperthermia was given by immersing the tumour-bearing murine feet into a water bath set at 41·5 ± 0·05°C for 60 min. Dose-response curves were obtained between the TG time and drug dose. The thermal enhancement ratio (TER) was expressed as a ratio of the slope of the dose-response curve obtained at 41·5°C to that obtained at room temperature. To evaluate normal tissue damage, the number of white blood cells (WBC) was counted from a day before treatment to the 21st day after treatment. A substantial thermal enhancement of the anti-tumour effect was observed in all five multidrug regimens tested. Glucose administered prior to thermochemotherapy further enhanced the antitumour effect. The TER was largest for the combination of CY+cDDP (TER was 5 without glucose). The second largest TER was obtained for a combination of CY+cDDP+MMC (TER was 4·1 without glucose and 6·5 with glucose). The antitumour effects of these two combinations were synergistic at a test elevated temperature only. No synergistic effect was found at room temperature for any of the drug combinations tested. The smaller TERs were observed in the treatment regimens that included SFU. In general, a decrease in the number of WBC following multidrug chemotherapy was slightly less than that following the individual drugs.     

Heat- and 4-hydroperoxy-ifosfamide-induced apoptosis in B cell precursor leukaemias

In the group of high risk childhood acute lymphoblastic leukaemia (ALL), very early and early relapses have a very poor prognosis with conventional chemotherapy alone. Remission induction in these patients is often hindered by drug resistance. Thus, intensifying chemotherapy strategies are required. Application of hyperthermia enhances efficacy of certain anti-neoplastic drugs such as ifosfamide. In this study, effects and molecular mechanisms of ifosfamide - and hyperthermia-induced apoptosis are investigated in a B cell precursor leukaemia cell line (REH) and in primary patient-derived B cell progenitor leukaemic blasts. Both 4OOH-IFA and hyperthermia are able to induce cell death in leukaemic cells, mainly by induction of caspase-dependent apoptosis. However, completely different kinetics of caspase-3, -8 and -9 activation are found for both stimuli. In addition, activation of caspase-1 is only observed following stimulation with hyperthermia. Combined application of ifosfamide and hyperthermia reveals increased cytotoxicity in both the leukaemia cell line and in 5/8 of the patient-derived leukaemic blast samples. In conclusion, hyperthermia and ifosfamide mediate cytotoxicity in B precursor leukaemic blasts by different kinetics of caspase activation. This might explain the additive effects of 4OOH-IFA and heat on leukaemic cell death. Therefore, whole body thermochemotherapy could be considered as a treatment option in relapsed leukaemic patients.     

热化疗对荷瘤鼠IL—2、TNF水平影响的研究

目的：探讨热化疗对荷瘤鼠IL－2、TNF水平的影响。方法：对正常Balb／c鼠及实验组荷瘤鼠脾脏IL－2、TNF水平进行检测。结果：热化疗组荷瘤鼠IL－2、TNF水平与正常鼠无显著性差异（P＞0．01），而与单纯热疗或单纯化疗及未作任何处理组比较有显著性差异(P＜0．01）。结论：热化疗可以提高荷瘤鼠IL－2、TNF水平，从而增强机体的免疫功能，提高机体全身抗肿瘤效应。     

超声对鼻咽癌拓扑替康热化疗的增效作用研究

目的以人鼻咽癌细胞株（CNE-2）为对象,观察超声对拓扑替康（TPT）热化疗作用的影响。方法计算TPT对CNE2的半数抑制浓度（IC50）后设单纯超声组、单纯TPT组、单纯热疗组、热疗＋TPT组、超声＋TPT热化疗组;记录各组数据得到生长抑制率,并在透射电镜下观察各组细胞的亚细结构变化。结果TPT对CNE-2的IC50为0．396μg／mL;热疗联合TPT对细胞的杀伤效应明显强于单纯TPT组,超声联合后抑制效应更为明显,组间比较差异有统计学意义（P〈0．01）;透射电镜显示超声＋TPT热化疗组的细胞损伤最严重,细胞器毁损特征明显。结论热疗对TPT有增效作用,超声增强了TPT热化疗的杀伤效应。     

肝动脉介入性热灌注化疗栓塞治疗不能手术切除的原发性肝癌近期疗效分析

目的探讨肝动脉介入性热灌注化疗栓塞治疗不能手术切除的原发性肝癌的近期疗效。方法 39例不能手术切除的原发性肝癌患者,经股动脉选择性肝动脉置管,采用表阿霉素(EADM)、5-氟尿嘧啶(5-FU)、丝裂霉素(MMC)、顺铂(CDDP)行热灌注化疗栓塞治疗,间隔40～50 d再次治疗,2次治疗后评价近期治疗效果及不良反应。结果 39例患者显效8例(20.5%),有效14例(35.9%),稳定15例(38.5%),进展2例(5.1%),总有效率为56.4%。AFP下降>50%者16例,其中11例恢复正常。结论肝动脉介入热灌注化疗栓塞治疗原发性肝癌安全有效,其远期疗效有待进一步观察。     

血清TSGF在妇科恶性肿瘤高能聚束热疗联合化疗中的表达及意义

[目的]观察恶性肿瘤相关物质群(TSGF)在妇科恶性肿瘤高能聚束热疗联合化学药物疗法(热化疗)中的表达并探讨其在疗效中的意义。[方法]采用比色法测定49例妇科恶性肿瘤患者进行热化疗治疗前、后肿瘤相关物质群的水平,并与47例对照组纯化学药物疗法治疗前后肿瘤相关物质群的水平进行比较。[结果]妇科恶性肿瘤患者治疗后肿瘤相关物质群水平明显下降,热化组治疗前后比较差异更为明显(P﹤0.01)。[结论]热化疗较纯化学药物疗法治疗妇科恶性肿瘤疗效更好,血清肿瘤相关物质群可作为观察妇科恶性肿瘤热化疗疗效及预后的重要指标之一。     

局部热化疗对大鼠胶质细胞移植瘤血管再生及VEGF表达的影响

目的　研究局部热化疗对鼠胶质细胞移植瘤血管再生及血管内皮生长因子 (VEGF)表达的影响 ,探讨其治疗胶质瘤的机制。方法　在鼠胶质细胞移植瘤动物模型上 ,分组进行局部热疗、化疗和热化疗。用FⅧ RA染色标记血管内皮细胞 ,以微血管密度作为定量检测指标。用免疫组化S P法检测VEGF蛋白表达 ;电镜观察肿瘤微血管结构的变化。结果　热疗、化疗、热化疗组与对照组比较 ,VEGF蛋白表达减低(P <0 .0 1) ,且热化疗有协同作用 (P <0 .0 1)。VEGF表达与MVD间呈正相关 (r=0 .9798,P <0 .0 0 1)。热化疗后肿瘤微血管外径变小 ,血管壁变厚 ,血管减少 ,血管内皮细胞紧密连接增多 ,细胞连接间隙减小 ,有的血管甚至只能发现完整的基膜而缺乏内皮细胞。结论　①热疗、化疗和热化疗能抑制肿瘤血管再生 ,且阿霉素与热疗有协同作用 ;②热化疗能降低肿瘤VEGF合成与分泌 ,破坏与减少肿瘤血管再生 ,作为胶质瘤辅助治疗有良好的临床应用前景     

阿霉素化疗与热化疗对人肺腺癌细胞株A549细胞抑制作用的比较研究

目的 探讨阿霉素（adriamycin，ADR）化疗与热化疗（热疗联合化疗）对人肺腺癌细胞株A549细胞的抑制作用与细胞内阿霉素浓度的关系。方法 不同浓度的阿霉素作用于体外培养的A549细胞，42．5℃作用30、60min后，37℃继续培养，然后用MTT法检测细胞的毒性作用，用流式细胞仪检测细胞内阿霉素浓度。结果 化疗、热化疗对A549细胞均有抑制作用，与对照组比较差异有非常显著性（P〈0．01），且均存在浓度、时间的依赖性；热化疗对细胞的抑制作用明显强于单纯化疗（P〈0．01）；热化疗组细胞内阿霉素的浓度明显高于单纯化疗组（P〈0．01）；各组细胞内药物浓度与细胞的抑制率呈直线相关（P〈0．05）。结论 阿霉素热化疗可以显著增强对A549细胞的抑制，其抑制作用与细胞内浓度有关。     

热化疗对晚期恶性肿瘤患者外周血CD8+CD28+ T细胞表达的影响及临床意义

 目的探讨热化疗对晚期肺癌、大肠癌、乳腺癌患者外周血CD8+CD28+T细胞亚群（CTL）表达的影响及临床意 义。方法晚期肺癌、乳腺癌、大肠癌患者各20例,随机分为热化疗与化疗两组,每组肺癌、乳腺癌、大肠癌患者各 10例,热化疗组每周期化疗予以同步全身热疗,至少完成两个周期治疗,正常健康志愿者20例作为健康对照,用流 式细胞仪检测外周血CD4+、CD8+、CD8+CD28+T细胞亚群。结果与健康对照组相比,肿瘤患者外周血T细胞CD4+ 、 CD8+及CD4+/CD8+的表达差异无统计学意义(P＞0.05),CD8+CD28+的表达显著降低(P＜0.05),热化疗组患者治疗后 T细胞CD8+CD28+表达上调,与治疗前比较差异有统计学意义（P＜0.05）,化疗组患者治疗前后T细胞CD8+CD28 +的 表达差异无统计学意义（P＞0.05）,热化疗组患者的有效率、生存质量优于化疗组患者（P＜0.05）, 两组治疗 的Ⅲ~Ⅳ度骨髓抑制及消化道反应比较差异无统计学意义（P＞0.05）,T细胞CD8+CD28+的表达与肿瘤病理类型无关 。结论晚期肿瘤患者T细胞存在共刺激分子CD28表达的低下及肿瘤细胞的免疫逃逸,热化疗能上调T细胞CD8+CD28+ 的表达,增强肿瘤患者的免疫监视功能,在疗效与预后上较化疗有优势。     

110℃碘化油-顺铂混悬剂超选择肝动脉化疗栓塞治疗中晚期肝癌术后不良反应及对患者生存期的影响

目的：观察110℃碘化油-顺铂混悬剂超选择肝动脉化疗栓塞治疗中晚期肝癌术后患者的临床不良反应的发生情况及该种治疗方法对患者生存期的影响。方法：跟踪随访对照组和实验组患者术后不良反应发生的情况及生存期的长短,进行回顾性对照分析。结果：实验组栓塞术后的发热、恶心、肝功能损害等不良反应程度较对照组略重,但差异无统计学意义,未发生特殊或严重的术后并发症及副反应。实验组的患者生存期较对照组延长,差异有统计学意义。结论：110℃碘化油-顺铂混悬剂超选择肝动脉化疗栓塞治疗中晚期肝癌能有效延长患者生存期,而无严重的不良反应及并发症,是一种利大于弊的有效治疗中晚期肝癌的介入治疗方法。