Hyperthermic Enhancement of Tumor Radiosensitization Strategies

Local hyperthermia of living tissue can cause significant increases in blood flow and oxygenation depending on time-temperature history. Increases in perfusion of the abnormal and insufficient vasculature found in solid tumors may increase tumor oxygenation, thereby increasing the radiation sensitivity of the tumor. We hypothesized that local heating of tumor would increase the oxygenation of the tumor tissue and allow other oxygenating agents to further modify tumor oxygenation and radiation response. In the present study the effect of moderate temperature hyperthermia (MTH) at 41.5–42.5°C for 30–60 min, 250 mg/kg nicotinamide, or carbogen breathing (95% O₂/5% CO₂) on the radiation sensitivity of FSaII murine fibrosarcomas or R3230 AC rat adenocarcinomas was studied. Individually, these treatments increased the tumor cell sensitivity to single dose 10–15 Gy X-irradiation by 1–5 fold on average, as measured by the in vivo/in vitro tumor excision assay. The combination of tumor MTH with nicotinamide or carbogen breathing increased the radiation sensitivity by 3–5 fold in FSaII tumors and 10–30 fold in R3230 tumors with varying levels of statistical significance. Finally, the triple combination of adjuvant MTH, nicotinamide and carbogen breathing increased the radiation-induced cell death in FSaII tumors to a similar extent as the dual combinations of MTH, nicotinamide or heat, carbogen breathing. However, in R3230 AC tumors the triple adjuvant combination significantly increased radiation-induced cell killing compared to all other dual adjuvant treatments (p < 0.04). To interrogate the mechanism by which heating alters tumor physiology, nitric oxide production in tumor and endothelial cells in culture and tumor tissue after heating was studied. Heating caused an increase in nitric oxide production over a 24 h period after treatment. Subsequently, inhibiting the enzymatic production of NO with L-NAME was found to increase heat-induced growth delay of FSaII tumors. The cause and effect of increased nitric oxide production and the response of the tumor vasculature to heat are discussed in the context of the tumor radiosensitization achieved by heating, carbogen breathing and nicotinamide.     

The Anti-Tumor Effect of Interleukin-12 is Enhanced by Mild (Fever-Range) Thermal Therapy

The cytokine interleukin 12 (IL-12) has resulted in notable anti-tumor activity in animal models and in patients and as a result there is considerable interest in learning how to maximize its therapeutic potential while at the same time reducing its known toxic side effects. Strategies which could maintain its effectiveness while permitting reduced dosage could be especially valuable. In this study we used BALB/c mice bearing CT26 tumors as a model for testing whether combining murine IL-12 with a mild (fever range) whole body hyperthermia protocol could result in such a strategy. Our data revealed that 100 ng of IL-12/mouse/day used in combination with FR-WBH was as effective as one in which 300 ng of IL-12/mouse/day was used alone. Importantly, the mice receiving the combination treatment exhibited fewer treatment related toxicities compared to those that received high dose IL-12 alone. Initiation of the IL-12 treatment immediately after FR-WBH induced the greatest anti-tumor effect. This effect does not appear to depend on differences in IL-12-induced IFN-γ, but may involve production of nitric oxide (NO), since treatment of mice with a NOS inhibitor, N^G-monomethyl-l-arginine (l-NMA), abolishes the additive anti-tumor effect of the combination treatment. Collectively, these data suggest that modification of physiological parameters in the host by mild fever-like thermal stimuli may be an effective and feasible adjuvant for cytokine-based immunotherapeutic strategies.     

Acute tumor lysis syndrome in high grade lymphoblastic lymphoma after a prolonged episode of fever

Acute tumor lysis syndrome occurs in rapidly growing lymphoid malignancies, usually as a consequence of chemotherapy or corticosteroids. We present what appears to be the first reported case of tumor lysis occurring after a sustained episode of high fever of 42.0°C in a patient with high grade lymphoblastic lymphoma and a high tumor burden. © 1996 Wiley-Liss, Inc.     

Multiple mitochondrial DNA deletions and persistent hyperthermia in a patient with Brachmann-de Lange phenotype

In a newborn boy with characteristics of Brachmann-de Lange syndrome (BDLS) high temperatures were observed on the second day after birth and recurred 2-6 times daily during the 7 months of the patient's life. After transient hypertonia hypotonia developed. In muscle biopsy specimen taken on the 51st day of life, serious and progressive distortion of mitochondria was observed. In several mitochondria the cristae structure was broken, other mitochondria were shrunken and the damage progressed towards further deterioration in other organelles. At several points between the myofibrils amorphous material was seen possible debris of destroyed mitochondria. Most myofibrils seemed to be intact; however, in some areas myolytic signs were present. Analysis of the mitochondrial DNA (mtDNA) showed multiple deletions in skeletal and heart muscles, liver, lung and kidney. Since the mtDNA encodes several proteins of the respiratory complexes, the deleted mtDNA certainly affected the integrity of the mitochondrial oxidative phosphorylation process by synthesis of abnormal proteins. In the present case the hyperthermia may have been a result of the mtDNA damage. © 1996 Wiley-Liss, Inc.     

体内γ刀、体外高频热疗、化疗联合治疗晚期肺癌36例疗效观察

目的 观察CT引导下组织间植入125I粒子联合体外高频热疗及化疗对晚期肺癌的疗效.方法 患者入院后先行肺穿刺活检或经支气管镜活检以明确肿瘤病理类型,经TPS计划系统计划后行体内γ刀治疗.3 d后行化疗(EP方案或顺铂 紫衫醇方案,每4周1次)及体外高频热疗(每周2次,共4周).所有患者术后第1、2、3、6、9、12个月内分别行胸部CT检查随访.根据肿瘤变化将疗效分为4级.Ⅰ级,明显缓解(肿瘤缩小50%以上).Ⅱ级,缓解(肿瘤缩小25%～50%).Ⅲ级,轻度缓解(肿瘤缩小1%～25%).Ⅳ级,无效(肿瘤无变化或增大,临床症状亦无缓解).V级,复发或转移.结果 术后第1、2、3、6、9、12个月明显缓解,分别占38.9%、66.7%、77.8%、83.3%、83.3%和77.8%.结论 体内γ刀、体外高频热疗、化疗联合治疗晚期肺癌是一种安全、可靠、疗效显著的治疗方法.     

高温复合脂多糖应激大鼠血清天门冬酸氨基转移酶的变化

目的:探讨高温与脂多糖(LPS)复合应激大鼠血清天门冬酸氨基转移酶(AST)含量的变化特点.方法:雄性SPF级Wistar大鼠64只随机均匀分为常温 生理盐水组(C组),高温 生理盐水组(H组),常温 LPS组(L组),高温 LPS组(HL组).置动物于模拟气候舱,HL和H组暴露环境干球温度(Tdb)为(35.0±0.5)℃,L和C组Tdb为(26±0.5)℃;HL和L组动物经尾静脉注射LPS 10 mg/kg,H和C组动物经尾静脉注射9 g/L NaCl 10 mL/kg.持续监测动物平均动脉压(MAP)的动态变化,检测动物应激0,40,80,120 min时血清AST等物质含量的变化.结果:AST在不同温度、时间、药物水平间存在统计学差异(P＜0.01);时间与温度、时间与药物、温度与药物交互作用有统计学意义(P＜0.05),120 min时相点HL组动物血清AST含量高于其余3组,差异有统计学意义(P＜0.01);AST水平与MAP存在负相关关系(r=-0.818,P=0.029).结论:高温与LPS复合应激可促发、扩大全身炎症反应综合征.