Therapeutic efficacy of targeting chemotherapy using local hyperthermia and thermosensitive liposome: evaluation of drug distribution in a rat glioma model.

A method was developed of targeting chemotherapy using thermosensitive liposomes to treat malignant gliomas. Using the brain heating system, when the tumour core is heated to >43 degrees C, the tumour infiltrating zone is exposed to mild hyperthermia (40-43 degrees C). Thermosensitive liposomes were designed to release their contents at 40 degrees C to target both the tumour core and tumour infiltrating zone. The present study investigated the anti-tumour effect on rat glioma models in tumour drug uptake and tumour growth delay studies. Elevated accumulation of ADR in the rat C6 glioma after treatment was obtained in the area heated to >40 degrees C. However, there was no significant difference between the areas heated to 40-42 degrees C and >43 degrees C. Furthermore, it was found that ADR concentrations in the mildly hyperthermic areas were significantly higher following treatment with liposomal ADR than with free ADR. The animals treated with the new combination therapy had significantly longer overall survival time in comparison to those receiving other treatments. Thus, thermosensitive liposomes release their contents in response to mild hyperthermia and this combination therapy has a greater therapeutic efficacy for malignant brain tumours. This method is a promising approach for the treatment of malignant glioma patients.     

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°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 necrotic 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.     

Mild hyperthermia plus adenoviral p53 over-expression additively inhibits the viability of human malignant glioma cells

Adenoviral replacement of the p53 gene has already been proved effective for the treatment of various tumours, including malignant gliomas. However, it is difficult to treat malignant glioma with p53 gene therapy alone because of problems with resistance or a less-than-satisfactory response to the treatment. This study investigated whether heat shock at 43°C (mild hyperthermia) augments the cytotoxic effect of p53 gene transfer on malignant glioma cells expressing wild-type p53 (D54) or mutant p53 (U373-MG and U251-MG). The combination of mild hyperthermia and adenoviral p53 over-expression had an additive inhibitory effect on cellular proliferation in all three cell lines studied. Further, both cell cycle analysis and a DNA fragmentation assay showed that apoptosis was induced by p53 over-expression alone but not by heat shock at 43°C alone. However, p53 over-expression followed by mild hyperthermia additively increased the proportion of cells in which apoptosis was induced, regardless of the endogenous p53 status of the tumour cells. Interestingly, a caspase-independent mechanism was observed to be involved in the p53-induced apoptosis in U251-MG and D54 cells. Taken together, the findings showed that combining adenoviral p53 transfer with mild hyperthermia inhibits the proliferation of malignant glioma cells in an additive manner, irrespective of their endogenous p53 status, suggesting a novel treatment strategy for this malignancy.     

Enhanced drug delivery in rabbit VX2 tumours using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia

Purpose: The efficacy of anticancer drugs in solid tumours is impaired by their inability to reach all cancer cells in sufficient concentration to cause cytotoxicity. Hyperthermia-triggered release of drugs from thermosensitive liposomes can increase tumour drug concentration, but tumour-specific drug delivery requires precise temperature control, and effects on microregional distribution of anticancer drugs in tumours are unknown. Here we evaluate thermally triggered release of doxorubicin in a rabbit tumour model by comparing free versus thermosensitive liposomal doxorubicin administered systemically during magnetic resonance imaging (MRI)-controlled focused ultrasound hyperthermia.

Materials and methods: Twelve rabbits with a transplanted VX2 tumour in each thigh had a 10?mm diameter region in one tumour heated to 43°C using focused ultrasound with temperature control by MRI thermometry. Delivery of doxorubicin to tumours and normal tissues was quantified by fluorescence in tissue homogenates, and by fluorescence microscopy.

Results: Using thermosensitive liposomal doxorubicin (2.5?mg/kg), doxorubicin concentrations in heated tumours were 26.7 times higher than in unheated tumours (n?=?7, p?=?0.017, two-sided Wilcoxon signed-rank test). There was no significant enhancement with free doxorubicin in heated versus unheated tumours (n?=?3, p?=?0.5). With thermosensitive liposomes (8.3?mg/kg), fluorescence microscopy demonstrated increased doxorubicin fluorescence in heated versus unheated tumours, co-localised with nuclear staining throughout the tumour.

Conclusions: Localised image-guided delivery of high concentrations of doxorubicin to cancer cells was achieved non-invasively in implanted tumours with temperature-sensitive drug carriers and a preclinical MRI-controlled focused ultrasound hyperthermia system.     

Mild hyperthermia plus adenoviral p53 over-expression additively inhibits the viability of human malignant glioma cells.

Adenoviral replacement of the p53 gene has already been proved effective for the treatment of various tumours, including malignant gliomas. However, it is difficult to treat malignant glioma with p53 gene therapy alone because of problems with resistance or a less-than-satisfactory response to the treatment. This study investigated whether heat shock at 43 degrees C (mild hyperthermia) augments the cytotoxic effect of p53 gene transfer on malignant glioma cells expressing wild-type p53 (D54) or mutant p53 (U373-MG and U251-MG). The combination of mild hyperthermia and adenoviral p53 over-expression had an additive inhibitory effect on cellular proliferation in all three cell lines studied. Further, both cell cycle analysis and a DNA fragmentation assay showed that apoptosis was induced by p53 over-expression alone but not by heat shock at 43 degrees C alone. However, p53 over-expression followed by mild hyperthermia additively increased the proportion of cells in which apoptosis was induced, regardless of the endogenous p53 status of the tumour cells. Interestingly, a caspase-independent mechanism was observed to be involved in the p53-induced apoptosis in U251-MG and D54 cells. Taken together, the findings showed that combining adenoviral p53 transfer with mild hyperthermia inhibits the proliferation of malignant glioma cells in an additive manner, irrespective of their endogenous p53 status, suggesting a novel treatment strategy for this malignancy.     

Intracellular Hyperthermia for Cancer Using Magnetite Cationic Liposomes: In vitro Study

'Magnetite cationic liposomes (MCL)' were developed as a means to generate intracellular hyperthermia. Affinity of the MCL to glioma cells was ten times higher than that of magnetite'neutral' liposomes due to the electrostatic interaction based on the positive charge of the MCL. Heat generation of the MCL was studied using agar phantoms and small pellets of rat glioma cells. When a high-frequency magnetic field, 118 kHz, 384 Oe was applied to glioma cells in the presence of MCL, the glioma cell pellet of 80 μl (5.4 mm in diameter) was heated to over 43°C and all the cells died after 40 min irradiation owing to the hyperthermic effect. The terminal temperature of the cell pellet was proportional to the pellet volume when other parameters were constant. It thus appears that the MCL can heat a tumor of more than 80 μl in volume to above 42°C.     

Encapsulation of doxorubicin in thermosensitive small unilamellar vesicle liposomes

The optimisation of the formulation of thermosensitive, doxorubicin-containing small unilamellar liposomes is described. The liposomes were first strictly defined in terms of size distribution and size stability and a quality level was defined. The suspension contained more than 95% vesicles with a maximal diameter of 50 nm and kept this level for a minimum of 24 hours. Several lipid mixtures were tested in defined thermal conditions usable for in vitro experiments: 43°C in fetal calf serum-containing medium. The mixture yielding the best differential thermal stability (DTS) defined as the difference of release between 37°C and 43°C exposures was found to be a dipalmitoylphosphatidylcholine/distearoylphosphatidyl-choline/cholesterol mixture in 5:4:2 molar ratio yielding 72% DTS. These thermosensitive liposomes were evaluated betwen pH 6.00 and 8.00 since hyperthermia-induced lethality was reported to be enhanced by pH variations. Their release capacity was not altered by any pH variations. Incorporation of doxorubicin within these liposomes was then performed. The release kinetics at 37° and 43°C were determined. It is proposed to use this formulation in in vitro experiments on tumour cells, although a decrease of DTS was evident.     

Thermotolerance in human glioma cells

Human glioma cells held in plateau phase were tested for the development of chronic and acute thermotolerance. Long duration, mild hyperthermia at 39–42°C for up to 48 h showed no development of chronic thermotolerance. Heating at 45°C immediately after mild hyperthermia showed that acute thermotolerance did develop for 40–42°C heating. This thermotolerance developed at about the same rate for the three inducing temperatures (40–42°C) but the decay characteristics were temperature dependent. In fact, for 42°C heating thermosensitization to subsequent 45°C heating was achieved after 48 h of heating. These data show that chronic and acute thermotolerance may be different in human glioma cells.     

Localised drug release using MRI-controlled focused ultrasound hyperthermia

Purpose: Thermosensitive liposomes provide a mechanism for triggering the local release of anticancer drugs, but this technology requires precise temperature control in targeted regions with minimal heating of surrounding tissue. The objective of this study was to evaluate the feasibility of using MRI-controlled focused ultrasound (FUS) and thermosensitive liposomes to achieve thermally mediated localised drug delivery in vivo.

Materials and methods: Results are reported from ten rabbits, where a FUS beam was scanned in a circular trajectory to heat 10–15?mm diameter regions in normal thigh to 43°C for 20–30?min. MRI thermometry was used for closed-loop feedback control to achieve temporally and spatially uniform heating. Lyso-thermosensitive liposomal doxorubicin was infused intravenously during hyperthermia. Unabsorbed liposomes were flushed from the vasculature by saline perfusion 2?h later, and tissue samples were harvested from heated and unheated thigh regions. The fluorescence intensity of the homogenised samples was used to calculate the concentration of doxorubicin in tissue.

Results: Closed-loop control of FUS heating using MRI thermometry achieved temperature distributions with mean, T90 and T10 of 42.9°C, 41.0°C and 44.8°C, respectively, over a period of 20?min. Doxorubicin concentrations were significantly higher in tissues sampled from heated than unheated regions of normal thigh muscle (8.3 versus 0.5?ng/mg, mean per-animal difference?=?7.8?ng/mg, P?<?0.05, Wilcoxon matched pairs signed rank test).

Conclusions: The results show the potential of MRI-controlled focused ultrasound hyperthermia for enhanced local drug delivery with temperature-sensitive drug carriers.     

Schedule dependent tumour growth delay,DNA cross-linking and pharmacokinetic parameters in target tissues with cis-diamminedichloroplatinum(II) and etanidazole with or without hyperthermia or radiation

It has been reported previously that striking increases in tumour growth delay and cytotoxicity are seen when cis-diamminedichloroplatinurn(II) (CDDP) is combined with mild local hyperthermia (43°C, 30 min) and/or etanidazole (ETA). This paper reports a study of CDDP pharmacology and the in vivo tumour DNA cross-linking produced by these combinations. In C3H mice bearing the FSaIIC murine fibrosarcoma, Pt plasma pharmacokinetics were not significantly altered by any of the combination of treatments. Although ETA caused no significant change in CDDP tissue pharmacokinetics, treatment of the tumour-bearing limb with hyperthermia immediately following an i.p. injection of CDDP (10 mg/kg) resulted in an increased peak Pt concentration (3.5 versus 2.8 μg Pt/g tumour wet weight) and doubled the t_1/2 elimination of Pt (15 to 30 h) from the tumour. Similar heat-induced changes were observed in the Pt pharmacokinetics in skin. There was about a three-fold increase in the Pt area under the curve (AUC) for the tumour, a 1.5-fold increase in the AUC for skin and little change in the AUC for muscle with hyperthermia. When the tumour DNA cross-linking factor (CLF) was determined, it was found that local hyperthermia treatment (43°C, 30 min) increased the CLF of CDDP from 1.7 to 2.7 and hyperthermia (43°C, 1 h) further increased the CLF to 6.1. Misonidazole (MISO) (1 g/kg) increased the CDDP CLF to 2.0, 6.3 and 15.1 in conjunction with 37, 43 (30 min) and 43°C (1 h), respectively. ETA (1 g/kg) was more effective than MISO at increasing the CDDP CLF, producing CLFs of 2.8, 9.1 and 21.5 at 37, 43 (30 min) and 43°C (1 h), respectively. These changes in CLF were reflected in an increased tumour growth delay in the FSaIIC murine fibrosarcoma with CDDP (5 mg/kg) alone from 4.4 to 5.9 days with 43°C (30 min) and then to 11.9 days with ETA (1 g/kg) and 20.9 days with both ETA and local hyperthermia (43°C, 30 min). When CDDP, ETA and hyperthermia were added to a radiation schedule of 300 cGy daily for five days, it was found that giving ETA (1 g/kg), CDDP (5 mg/kg) and hyperthermia (43°C, 30 min) together on day 1 produced the largest tumour growth delay (43 days) and that other schedules which divided the dose of ETA over the other days of the radiation treatment (including one schedule with a second heat treatment on day 4) were significantly inferior. Thus, local hyperthermia increased tumour versus normal tissue exposure to Pt, probably by altering the vascular physiology of the tumour, and both hyperthermia and ETA markedly increased CDDP-induced DNA damage, leading to commensurate increases in tumour growth delay. These results suggest that the addition of both ETA and hyperthermia to CDDP should be effective clinically, and they indicate that treatment once a week with hyperthermia, CDDP and ETA at the maximum tolerated dose will be the most successful.     

Antitumour effect of interferon combined with hyperthermia against experimental brain tumour

Antiproliferative activity of recombinant murine interferon-beta (Rec-MuIFN-beta) combined with hyperthermia against Rous sarcoma virus-induced mouse malignant glioma (RSV glioma) was investigated both in vitro and in vivo. In vitro, the antiproliferative activity of Rec-MuIFN-beta was enhanced by incubation at elevated temperatures (40 degrees and 43 degrees C). In vivo, combined therapy of Rec-MuIFN-beta treatment and local tumour hyperthermia (43 degrees C) exerted a greater antitumour effect against transplanted RSV glioma in C3H/He mice than either treatment alone, especially when Rec-MuIFN-beta was administered intratumourally. Subsequently, in order to probe the mechanism of enhanced antiproliferative activity, the production of prostaglandin E2 (PGE2) and 2', 5'-oligoadenylate synthetase (2-5A synthetase) in the culture medium of RSV glioma cells was measured. Rec-MuIFN-beta treatment resulted in a significantly greater PGE2 and 2-5A synthetase production at 43 degrees C than at 37 degrees C.     

Thermal therapy of pancreatic tumours using endoluminal ultrasound: Parametric and patient-specific modelling

Purpose: The aim of this study is to investigate endoluminal ultrasound applicator configurations for volumetric thermal ablation and hyperthermia of pancreatic tumours using 3D acoustic and biothermal finite element models. Materials and methods: Parametric studies compared endoluminal heating performance for varying applicator transducer configurations (planar, curvilinear-focused, or radial-diverging), frequencies (1–5 MHz), and anatomical conditions. Patient-specific pancreatic head and body tumour models were used to evaluate feasibility of generating hyperthermia and thermal ablation using an applicator positioned in the duodenal or stomach lumen. Temperature and thermal dose were calculated to define ablation (>?240 EM_43?°C) and moderate hyperthermia (40–45?°C) boundaries, and to assess sparing of sensitive tissues. Proportional-integral control was incorporated to regulate maximum temperature to 70–80?°C for ablation and 45?°C for hyperthermia in target regions.

Results: Parametric studies indicated that 1–3 MHz planar transducers are the most suitable for volumetric ablation, producing 5–8?cm³ lesion volumes for a stationary 5-min sonication. Curvilinear-focused geometries produce more localised ablation to 20–45?mm depth from the GI tract and enhance thermal sparing (T_max?<?42?°C) of the luminal wall. Patient anatomy simulations show feasibility in ablating 60.1–92.9% of head/body tumour volumes (4.3–37.2?cm³) with dose?<?15 EM_43?°C in the luminal wall for 18–48 min treatment durations, using 1–3 applicator placements in GI lumen. For hyperthermia, planar and radial-diverging transducers could maintain up to 8?cm³ and 15?cm³ of tissue, respectively, between 40–45?°C for a single applicator placement. Conclusions: Modelling studies indicate the feasibility of endoluminal ultrasound for volumetric thermal ablation or hyperthermia treatment of pancreatic tumour tissue.     

Mild thermotolerance induced at 40 °C protects cells against hyperthermia-induced pro-apoptotic changes in Bcl-2 family proteins

Purpose: Despite clinical progress, mechanisms involved in cellular responses to low and high doses of hyperthermia are not entirely clear. This study investigates the role of Bcl-2 family proteins in control of the mitochondrial pathway of apoptosis during hyperthermia at 42–43?°C and the protective effect of a low dose adaptive survival response, mild thermotolerance induced at 40?°C.

Materials and methods: Levels of Bcl-2 family proteins were detected in HeLa cells by western blotting, caspase activation by spectrofluorimetry and apoptosis by chromatin condensation.

Results: Hyperthermia (42–43?°C) decreased total and mitochondrial expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, while expression of pro-apoptotic proteins Bax, Bak, Puma and Noxa increased. Hyperthermia perturbed the equilibrium between these anti- and pro-apoptotic Bcl-2 family proteins in favour of pro-apoptotic conditions. Hyperthermia also caused activation of caspases-9 and -3, and chromatin condensation. Disruption of the balance between Bcl-2 family proteins was reversed in thermotolerant (40?°C) cells, thus favouring cell survival. Bcl-2/Bcl-xL inhibitor ABT-737 sensitised cells to apoptosis, which indicates that Bcl-2 family proteins play a role in hyperthermia-induced apoptosis. The adaptive response of mild thermotolerance (40?°C) was still able to protect cells against hyperthermia (42–43?°C) when Bcl-2/Bcl-xL were inhibited.

Conclusions: These results improve knowledge about the role of Bcl-2 family proteins in cellular apoptotic responses to hyperthermia (42–43?°C), as well as the adaptive survival response induced by exposure to mild stresses, such as a fever temperature (40?°C). This study could provide rationale to explore the manipulation of Bcl-2 family proteins for increasing tumour sensitivity to hyperthermia.     

Changes in hepatic blood flow during regional hyperthermia

The influence of liver hyperthermia on hepatic arterial and portal venous blood flow to tumour and normal hepatic tissue was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450 MHz microwave generator to exteriorized livers in 18 rabbits. Blood flow was measured in both portal vein and hepatic artery using radioactive tracer microspheres before, during and 5 min after intense (>43°C) hyperthermia. During hyperthermia a decrease in total liver blood flow was composed primarily of a decrease in hepatic arterial blood flow to tumour tissue. Tumours were supplied almost exclusively by the hepatic artery and thus total tumour blood flow was significantly depressed during heating. The decreased tumour blood flow persisted after the cessation of hyperthermia and was indicative of vascular collapse in the tumour tissue. Temperature differentials in tumour compared to normal tissue ranged from 5°C to 8°C during hyperthermia because of the lower tumour blood flow. The portal vein exerted minimal influence on temperatures attained in the tumour tissue during hyperthermia but would have mediated normal liver tissue heat loss.     

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.     

Hyperthermia induces apoptosis in malignant fibrous histiocytoma cells in vitro

The effect of mild hyperthermia on a cultured rat malignant fibrous histiocytoma (MFH) cell line, MFH-2NR, was investigated. MFH cells in log-phase (growing phase) were heated at 41°–44°C for 1 hr. Hyperthermic treatment at 41°C did not substantially affect cell proliferation and treatment at 44°C caused necrosis. After hyperthermic treatment at 42° or 43°C, proliferation of MFH cells was arrested and morphological changes characteristic of apoptosis, cell shrinkage accompanying apoptotic bodies and chromatin condensation, became apparent. Hyperthermia-induced apoptosis was further confirmed by terminal deoxynucleotidyl transferase staining and a ladder pattern on agarose gel electrophoresis. Flow cytometric analysis indicated that the population in the G₁ phase of the cell cycle significantly decreased with a concomitant increase in apoptotic cells, indicating that apoptosis might occur mainly in the G₁ phase population. © 1996 Wiley-Liss, Inc.     

Temporal dependence of hyperthermic augmentation of macrophage-TNF production and tumor cell-TNF sensitization

Hyperthermia in the therapeutic (±42–43 °C) and febrile (±39–40.5°C) ranges modulated the cytotoxic activities of macrophages cocultured with tumour cells and of the monokine tumour necrosis factor (TNF) against tumour cells. These modulatory interactions had clear treatment-sequence dependencies, and some sequences markedly augmented cytotoxic activities. Heated murine bacillus Calmette-Guerin-activated macrophages retained their cytotoxic activities better in coculture with unheated tumour cells if triggering with the endotoxin lipopolysaccharide preceded 1 h of heating at 42 or 43°C than they did if heating to the same extent was concomitant with, or preceded, triggering. Retention of cytotoxicity in coculture during 24 h of 39 or 40.5°C heating was less dependent on pre-heating triggering. The triggering/heating sequence also had modulatory effects on the secretion by heated macrophages of TNF which is involved in cytotoxic manifestations in coculture. Production of TNF by macrophages heated for 1 h at 40.5–43°C or 24 h at 39 or 40.5°C was augmented 1.5- to 6-fold (depending on the heat dose) when triggering preceded heating, whereas sequences in which heating was concomitant with triggering or preceded triggering were detrimental to TNF secretion. Profound treatment-sequence dependencies were also seen when timing of the addition of recombinant human TNF was varied in relation to the heat treatment of tumour cells. Sensitization of TNF-responsive L-929 and TNF-resistant EMT-6 tumour cells occurred if monokine addition preceded heating, whereas the reverse treatment-sequence reduced or eliminated sensitization. Both tumour cell types were also sensitized to TNF if monokine treatment preceded 24 h heating at 40.5 °C. These results support the hypothesis that appropriately constructed sequences for either macrophage priming/triggering or monokine treatment of tumour cells, combined with hyperthermia, could augment the cytotoxic actions of macrophages and the cytotoxicity of endogenously added monokines.     

Physikalische und technische Grundlagen der regionalen Tiefenhyperthermie

Regional deep hyperthermia (RHT) places special demands on therapists: a tumour deep within the body must be heated up to 43°C (or more) and healthy tissue must be preserved, so special difficulties arise. Usually RHT is given by radiant radio frequency hyperthermia systems. The procedure can be rendered more effective by using hyperthermia treatment planning systems: planning assists therapists in the selection of those patients who can be treated effectively and makes it possible to raise the temperature up to 1°C higher with the same side effects in the optimal case. That can lead to increased efficiency, theoretically up to 100%. If the recommended temperature control during treatment is done by noninvasive 3-D MR thermometry, further improvement can potentially result. With the additional 3-D information from the images hyperthermia planning can be adapted to the actual situation, as image-guided RHT.     

Enhancement of the therapeutic outcome of radio-immunotherapy by combination with whole-body mild hyperthermia

To enhance the effect of radio-immunotherapy for solid cancers, whole-body mild hyperthermia was added, and its effects on the pharmacokinetics of radiolabelled antibody, outcome of radio-immunotherapy, and radiosensitivity of the tumour were investigated. Nude mice bearing human colon cancer xenografts were heated to 40°C for 3 or 6 h. After heating, mice received intravenous (i.v.) injections of [¹³¹I]-labelled anti-carcinoembryonic antigen (CEA) monoclonal antibody. Although 6-h heating did not alter the biodistribution of the radiolabelled antibody, and alone did not show any therapeutic effect on tumour growth, when combined with radio-immunotherapy, the therapeutic effect on tumour growth was significantly enhanced. Three-hour heating also significantly enhanced the effect of radio-immunotherapy. Colony formation assay showed that the radiosensitivity of the tumour was significantly enhanced after heating, which was achieved by a reduction of the hypoxic fraction of the tumour. In conclusion, the addition of whole-body mild hyperthermia significantly enhanced the therapeutic effect of radio-immunotherapy by increasing the radiosensitivity of the tumour.