Effects of adenosine 3′, 5′-cyclic monophosphate on thermoregulation in both rats and rabbits

Summary The effects of intraventricular administration of dibutyryl adenosine 3, 5-cyclic monophosphate (db cyclic AMP) on the thermoregulatory responses of unanesthetized rats and rabbits to different ambient temperatures (T_a) were assessed. Administration of db cyclic AMP (10–60 mM) produced dose-dependent hypothermia in both rats and rabbits at T_a 2–22 °C. The hypothermia in response to db cyclic AMP was due to decreased metabolic heat production and cutaneous vasodilatation. There was no change in respiratory evaporative heat loss. In contrast, in the heat (30–32 °C), db cyclic AMP administration produced dose-dependent hyperthermia in these animals. The hyperthermia was due to increased metabolism (due to muscular shivering) and decreased heat losses. The reduction in heat losses was shown by a decrease in both cutaneous circulation and respiratory evaporative heat loss. The data demonstrate that the thermoregulatory responses induced by central administration of db cyclic AMP are T_a-dependent.     

恶性肿瘤放疗加超声热疗的近期疗效

目的 :研究放疗结合超声热疗治疗恶性肿瘤的疗效及毒副反应。方法 :1997年 1月～ 2 0 0 0年 1月间4 1例经病理证实的局部晚期、复发 /转移或对放射敏感性差的表浅性恶性肿瘤患者接受放疗加超声热疗 ,放疗均采用外照射 ,平均剂量 (6 1± 12 )Gy ,热疗于放疗结束后 30分钟内进行 ,1～ 2次 /周 ,平均加热时间为 (5 2 .4± 6 )分钟 ,平均加热 (4.9± 2 .2 )次。采用方差分析肿瘤消退率与热疗参数的关系 ;Kaplan Meier、Cox回归分析三年局部控制率、生存率和预后因素的影响。结果 :CR、PR、NC间的Tmin、Tmax值差异具有统计学意义。全组肿瘤局部CR为 5 8.5 % ,三年局控率、生存率分别为 13.6 %和 32 .6 9%。Tmin、肿瘤体积、放射剂量对三年局控率有显著性影响 (P <0 .0 5 )。超声热疗配合放疗毒副反应较轻。结论 :Tave、Tmax、Tmin、Tmax等参数可用于反映、评价热疗效果 ,放疗结合超声热疗为治疗晚期表浅性恶性肿瘤的有效方法 ,毒性小 ,值得进一步研究。     

高温对人舌癌细胞粘附性影响的实验研究

[目的]观察高温外理前、后的人舌癌细胞(Tca鄄8113)对层粘连蛋白(Ln)和纤维粘连蛋白(Fn)的粘附能力的影响,探寻高温治癌的机理。[方法]采用结晶紫染色法分别测定在37℃条件下培养24小时和在43℃条件下加热40分钟后继续培养24小时的Tca鄄8113细胞对Ln和Fn的粘附能力。[结果]加温后的人舌癌细胞粘附在包被了Fn和Ln孔板上的数量、密度明显减小;通过酶标仪测定光密度OD值,发现加温组的OD值均低于未加温组的OD值,两组相比,具有显著性差异(P<0.01)。[结论]高温能够降低人舌癌细胞对Fn、Ln的粘附能力,从而降低肿瘤细胞对基底膜的浸润、转移力,达到治疗肿瘤的目的。     

Phase I study of combined radiation, hyperthermia and intra-arterial carboplatin for local recurrence of cervical cancer.

BACKGROUND: Patients with cervical cancer who develop pelvic recurrence after primary surgery are usually treated with radiation-based therapy. However, their prognoses are dismal. We conducted a phase I study of combined radiation, hyperthermia and intra-arterial (IA) carboplatin for local recurrence of cervical cancer. PATIENTS AND METHODS: Patients with local recurrence of cervical cancer without extrapelvic recurrence were included in this study. Carboplatin was given as a 5-min IA infusion without hydration just before pelvic radiation every day. External pelvic irradiation (1.8 Gy/day for 28 days) was performed according to local standard schedules. After 20 Gy had been administered, hyperthermia was performed once a week with a radio frequency heating system for four cycles. RESULTS: Fifteen patients were entered through the four dose levels of carboplatin. The maximum tolerated dose was determined to be 25 mg/m(2 )and the dose-limiting toxicities were leukocytopenia, neutrocytopenia and diarrhea. Grade 3/4 leukocytopenia and diarrhea were observed in nine (60%) and three (20%) of 15 patients. Tumor responses included five complete responses and nine partial responses, and the overall response rate was 93.3% (14 of 15) (95% confidence interval 59.4% to 100%). Tumor reductions were observed only at 20 Gy in 10 cases of 14 responders (71.4%). CONCLUSION: The combination therapy of radiation, hyperthermia and IA carboplatin is safe and well-tolerated for locally recurrent cervical cancer.     

Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification

Malignant gliomas have been associated with a high rate of glycolytic activity which is believed necessary to sustain cellular function and integrity. Since lonidamine (LND) is believed to reduce tumor glucose utilization by inhibition of the mitochondrially-bound glycolytic enzyme hexokinase (HK), ³¹P magnetic resonance spectroscopy (MRS) was used to noninvasively follow the effects of LND on both tumor pH and the high-energy phosphate metabolites; ATP, phosphocreatine (PCr) and inorganic phosphate (P_i) in subcutaneous rat 9L gliosarcomas. ³¹P tumor spectra acquired in 5 min intervals pre- and post LND administration of 50 and 100 mg/kg, i.p. revealed an acidotic pH shift of – 0.25 and – 0.45 pH units, respectively within 30 min post administration. The ATP/P_i ratio of 9L tumors decreased to 40% of control and P_i levels increased to 280% of control over a 3 hr period. LND exerted no effect on tumor blood flow and mean arterial blood pressure. Brain and muscle metabolite levels and pH were also unaffected by LND. In vitro measurements of cultured 9L tumor cell intra- and extracellular lactate, pentose phosphate pathway (PPP) and hexokinase (HK) activities suggest that the mode of action of LND involves inhibition of lactate efflux and intracellular acidification. The selective reduction of tumor energy metabolites and pH by LND may be exploitable for sensitizing gliomas to radiation, chemotherapy or hyperthermia.     

Antitumor Immunity Induction by Intracellular Hyperthermia Using Magnetite Cationic Liposomes

Induction of antitumor immunity to T-9 rat glioma by intracellular hyperthermia using functional magnetic particles was investigated. Magnetite cationic liposomes (MCLs), which have a positive surface charge, were used as heating mediators for intracellular hyperthermia. Solid T-9 glioma tissues were formed subcutaneously on both femurs of female F344 rats, and MCLs were injected via a needle only into the left solid tumors (treatment side). The rats were then divided into two groups, which received no irradiation, or irradiation for 30 min given three times at 24-h intervals with an alternating magnetic field (118 kHz, 384 Oe). On the treatment side, the tumor tissue disappeared completely in many rats exposed to the magnetic field. The tumor tissue on the opposite side also disappeared completely, even though MCLs were not injected into the right solid tumors. To examine whether a long-lasting and tumor-specific immunity could be generated, the rats that had been cured by the hyperthermia treatment were rechallenged with T-9 cells 3 months later. After a period of transient growth, all tumors disappeared. Furthermore, immuno-cytochemical assay revealed that the immune response induced by the hyperthermia treatment was mediated by both CD8⁺ and CD4⁺ T cells and accompanied by a marked augmentation of tumor-selective cytotoxic T lymphocyte activity. These results suggest that our magnetic particles are potentially effective tools for hyperthermic treatment of solid tumors, because in addition to killing of the tumor cells by heat, a host immune response is induced.     

Postischemic spontaneous hyperthermia and its effects in middle cerebral artery occlusion in the rat

This study examined the time course and effects of postischemic spontaneous hyperthermia after transient and permanent focal ischemia. Rats underwent a 90-min, 120-min, or permanent middle cerebral artery occlusion (MCAO). Body temperatures started rising 15-20 min after MCAO and reached 39-40.5 degrees C during the first hour. Sustained hyperthermia was observed during the rest of the first 24 h. In another experiment, rats were subjected to the same interventions, but a normothermic body temperature was maintained. Spontaneous hyperthermia significantly increased the infarct volumes measured 48 h after MCAO in all groups. Reperfusion 2 h after the onset of ischemia was not beneficial in the hyperthermic animals in contrast to the normothermic group. We also examined the effect of spontaneous hyperthermia on the temporal progression of infarcted and penumbral areas 4, 12, or 48 h after MCAO. During spontaneous hyperthermia, penumbral areas became infarcted areas more rapidly, which was most expressed at 4 h. These findings demonstrate that severe spontaneous hyperthermia can occur in rats after MCAO and that it not only increases the infarct volumes in both transient and permanent ischemia, but also accelerates the incorporation of penumbral areas into necrotic areas, which significantly decreases the window of opportunity for therapeutic interventions.     

热毒平抗脂质过氧化及对腹腔巨噬细胞凋亡影响

目的研究热毒平抗脂质过氧化以及对腹腔巨噬细胞(macrophage,Mφ)凋亡的影响,为热毒平治疗重症中暑提供实验依据。方法昆明种小鼠50只,随机分为常温对照组、热毒平组、西黄芪胶组、生理盐水组和中暑模型组。在干球温度(34.5±0.5)℃,相对湿度(60±5)%的条件下建立中暑模型,测定用药组和对照组小鼠肝组织超氧化物歧化酶(SOD)活力、丙二醛(MDA)含量;提取动物腹腔巨噬细胞DNA并行凝胶电泳;用流式细胞仪检测各组小鼠腹腔Mφ凋亡情况。结果热毒平均小鼠肝组织SOD活力升高,MDA含量降低;DNA电泳图中热毒平组无梯状条带;热毒平组腹腔Mφ凋亡百分率比其他组低且接近正常组。结论热毒平能有效的防止高温所致的脂质过氧化、减少其腹腔Mφ凋亡,对重症中暑有着良好的治疗作用。     

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.     

进展期结直肠癌术后腹腔热灌注化疗联合静脉化疗的临床研究

目的观察和比较腹腔热灌注化疗联合静脉化疗与单纯静脉化疗对进展期大肠癌术后腹腔局部复发、肝转移率及3年生存率的影响和不良反应。方法将90例大肠癌根治术后的进展期结直肠癌患者随机分成腹腔热灌注化疗联合静脉化疗组（治疗组）和静脉化疗组（对照组）,比较其疗效和生存率。结果治疗组3年腹腔局部复发率、肝转移率及3年生存率分别为15．6％、8．9％、82．2％,而对照组为37．8％、26．7％、62．2％,差异均有统计学意义（P〈0．05）,两组不良反应差异无统计学意义（P〉0．05）。结论影响进展期大肠癌术后生存率的主要原因是癌细胞的肝转移和腹腔局部复发,而腹腔热灌注化疗联合静脉化疗是预防进展期大肠癌术后肝转移和腹腔局部复发非常有效的方法。