Combination therapy of rat brain tumours using localized interstitial hyperthermia and intra-arterial chemotherapy.

Several investigators have reported that a high concentration of drugs in a tumour can be achieved using intra-arterial (IA) chemotherapy. This treatment was highly effective, especially in brain tumours, but the actual therapeutic advantage is still unknown. There are also indications that human malignant gliomas can effectively be treated using interstitial hyperthermia. Therefore, a combined treatment of IA chemotherapy and interstitial hyperthermia should be very promising and this has been studied in a tumour model. Wistar rats with isotransplanted C(6) gliomas in the brain were treated with adriamycin (ADR, 1.0 mg/kg body weight) either infused via the carotid artery (i.a.) or via the tail vein (i.v.), with or without interstitial hyperthermia. Hyperthermia of the tumours was applied using a homemade radiofrequency antenna (RF-heating) and a heating device that maintained the tumour temperature above 40 degrees C. Concentration of adriamycin in tumours after treatment was measured using HPLC. The effectiveness of treatment was determined by the survival time of the animals and histopathological examinations. The highest uptake of adriamycin in the rat C(6) glioma was obtained when the animals were treated with hyperthermia and i.a. ADR infusion (p <0.01). These animals also showed significantly longer overall survival time (SF50 =46 days) in comparison to the other treatments (p < 0.05). The histological studies demonstrated a necroti c tumour; however, the surrounding normal brain tissue remained intact. Thus, a combination of IA chemotherapy with adriamycin and localized interstitial hyperthermia enhances considerably the efficacy of adriamycin and has a greater antitumour effect for malignant brain tumours. This method is suitable for clinical use, and may be a new strategy for treating gliomas not successfully treated today.

Planning of hyperthermic treatment for malignant glioma using computer simulation.

Interstitial hyperthermia was applied using a radiofrequency generator in the treatment of four malignant glioma patients who had especially deep seated brain tumours or were at high risk. Prior to heating tumours, treatment planning based on an accurate prediction of temperature distribution is essential. The present paper introduces a novel treatment planning method and discusses its clinical efficacy. The two-dimensional finite element method was used for simulation of temperature distribution, which was calculated using the bioheat transfer equation. This technique was applied to plan treatment. Temperature was measured at two points during heating and these values were compared with those estimated by the simulation. In addition, the area of the contrast enhanced (CE) rim on the pre-heating computed tomography (CT) image was compared with the low density area of the CE rim on the post-heating CT image, which was obtained within 2 months after heating. The optimal position and number of radiofrequency (RF) electrodes to include the outside of the CE rim in the simulated area above 42 degrees C contour could be easily determined using this planning system in all cases. The temperature estimated by the simulation was in good agreement with the actual values obtained (within 0.4 degrees C). The post-heating CT image revealed that the hyperthermic procedure described herein achieved more than an 80% low density area within the CE rim in all cases (mean 86.0%). These results demonstrate that this novel treatment planning method may prove to be a clinically valuable tool in the treatment of malignant glioma with RF electrodes.

Synthesis of NG-061 and its analogs, and their biological evaluation as an enhancer of nerve growth factor.

A novel potentiator of nerve growth factor (NGF), NG-061, which had been isolated from the fermentation broth of Penicillium minioluteum F-4627, was synthesized from methoxybenzoquinone and phenylacetylhydrazine in a single step. A series of acyl hydrazone derivatives were also synthesized and their potentiator activity of neurotrophic effect of NGF on neurite outgrowth was evaluated by assay with a rat pheochromocytoma cell line PC12.

Effects of whole-body hyperthermia on the canine central nervous system.

It has been reported that central nervous system (CNS) tissue may be more heat labile than other tissues of the body. However, no definite information has been available on how much heat CNS tissue can tolerate without sustaining damage during whole-body hyperthermia, especially in a chronic stage. In this study, whole-body hyperthermia was induced in dogs by extracorporeal heating of blood, to determine the effects 7 days after hyperthermia on the canine brain and spinal cord. The temperatures of both the brain and the spinal cord were raised to 42.0+/-0.1 degrees C and maintained at that level for 60 min. Seven days later, all of the dogs were sacrificed by transcardial perfusion using 10% formaldehyde phosphate buffer for microscopic examination. The thermal dose resulted in neither microscopic damage to the CNS nor neurological symptoms, as determined by comparison of microscopic and neurological findings with those of dogs whose brain and spinal cord temperatures were maintained at 37.0 degrees C for 60 min. The findings suggest that, for medical purposes, whole-body hyperthermia appears promising for application at a thermal dose of up to 42.0 degrees C for 60 min.

Hyperthermic sensitization by hematoporphyrin on glioma cells.

This study investigated: (1) the effect of Hp as a hyperthermic sensitizer on glioma cells; and (2) the possible mechanism of hyperthermic sensitization by Hp using an exogenous scavenger specific to a particular reactive oxygen species. Hp at nontoxic doses at 37 degrees C significantly enhanced thermal cell damage at 41.5 degrees C and above in a dose-dependent manner. Thermal cell damage enhancement by HP was effectively suppressed by the addition of beta-carotene, a singlet oxygen scavenger, or SOD, a superoxide scavenger, but not by the addition of mannitol or catalase. These results support the following hypothesis: The generation of superoxide is increased in cells treated with Hp in combination with hyperthermia. Thermal cell damage enhancement by Hp is probably mediated by singlet oxygen generated via superoxide in an alternative pathway different from that of photosensitization. Hp has potential as a hyperthermic sensitizer because of the following advantages: (1) its dose-dependent enhancement of thermal cell damage; and (2) the lack of toxicity at physiological temperature at doses of Hp required for hyperthermic sensitization of tumour cells.

Targeting chemotherapy for malignant brain tumor using thermosensitive liposome and localized hyperthermia.

Thermosensitive liposomes are microscopic vesicles that can contain drugs and release them effectively in response to hyperthermia. To deliver an antitumor drug specifically to brain tumor, the authors used thermosensitive liposomes containing cis-diamminedichloroplatinum (CDDP) in conjunction with localized brain heating. The authors then investigated the antitumor effect on rat malignant glioma. Rous sarcoma virus-induced malignant glioma cells were transplanted into the brains of Fisher rats. Ten days after tumor inoculation, the rats were assigned to one of six treatment groups: control, free CDDP, hyperthermia, free CDDP + hyperthermia, liposomes containing CDDP (CDDP-liposome), and CDDP-liposome + hyperthermia. Liposomes containing CDDP or free CDDP were injected via the tail vein. Brain tumor heating was administered by means of a radiofrequency antenna designed at our institute. The rats treated with CDDP-liposome + hyperthermia had the longest survival time and the tumor CDDP level of this group was the highest when compared to the other groups. Histopathological examination showed that tumor cells were necrotized but surrounding normal brain tissue remained undamaged. On the basis of these findings we suggest that the combination of thermosensitive liposome and localized hyperthermia may better focus antitumor drugs to the tumor, providing a significantly greater antitumor effect.

Drug delivery to the brain using thermosensitive liposome and local hyperthermia.

We investigated the possibilities of drug delivery to the brain using thermosensitive liposomes and hyperthermia. Thermosensitive liposomes are small vesicles containing some drugs, which are designed to release the drugs in response to hyperthermia. The first experiment consisted of four groups: (1) received free Cisplatin: cis-diamminedichloroplatinum (CDDP); (2) received free CDDP and above 41 degrees C local brain heating for 30 min; (3) received liposomes containing CDDP (CDDP-liposome); and (4) received CDDP-liposome and above 41 degrees C local brain heating for 30 min. Brain CDDP levels were significantly higher in (4), while those on the other groups were undetectable. In the second experiment, we studied the distribution of Evans blue (Eb) in the artificially heated region of mongrel dogs' brain. One group received free Eb and the other group received liposomes containing Eb (Eb-liposome). While the extravasation of free Eb was localized in regions heated > 44 degrees C, that of Eb-liposome was extended up to the regions heated at 41 degrees C. We concluded that the use of thermosensitive liposomes and hyperthermia not only contributes to the brain tumour killing as direct thermal killing does but also helps to increase the concentration of chemotherapeutic drugs into the tumour invaded zones with mild local hyperthermia of 41 degrees C.