The influence of misonidazole on the radiation response of murine tumors of different size: possible artifacts caused by pentobarbital sodium anesthesia.
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Adenocarcinoma↗
Biomedical subjects
J Wondergem
Publications and source records attributed to J Wondergem.
Effects of 434 MHz microwave hyperthermia applied to the rat in the region of the cervical spinal cord.
Hyperthermia was applied in the region of the vertebral column between the cervical vertebrae 5 and thoracic 2, using a ring-shaped applicator operating at a microwave frequency of 434 MHz. This region was focally heated, including spinal cord, vertebrae, intervertebral discs and nerve roots. In all experiments temperature was measured at a 'reference' thermocouple probe which was placed against one of the cervical vertebrae 6, 7 or thoracic 1. Temperatures inside the vertebral canal were measured separately and proved to be below the 'reference' temperature: at 42 degrees, 43 degrees, 44 degrees and 45 degrees C (+/- 0.1 degree C) respectively the temperature in the canal was 41.2 degrees, 42.3 degrees, 42.9 degrees and 43.2 degrees C (+/- 0.4 degree C). Temperatures in tissues close to the vertebrae (e.g. within 2 mm lateral to the vertebrae, in the region of the brachial plexus) did not differ significantly from the temperature inside the canal. The temperature inside the intervertebral disc was as high as the 'reference' temperature. Temperatures measured at other sites, e.g. in the oesophagus, rectally and in the cervical muscles 5 or 10 mm lateral from the vertebral column showed that these sites were only slightly heated. The effects of hyperthermia at temperatures inside the spinal canal ranging from 41.2-43.2 degrees C for 30-120 min were investigated. One day after treatment at 41.2 degrees C for 120 min or 42.3 degrees C for 60 min neither neurological symptoms nor deaths were observed. Minor neurological symptoms were observed one day after 75 min at 42.3 degrees C. The incidence and severity of the neurological symptoms (ranging from unco-ordinated use of the forelegs to paralysis) increased with increasing temperature and duration of the hyperthermic treatment. Thermal damage even resulted in lethality: 74 per cent of the rats that died did so between 2 and 42 h after treatment. The LD50 value at 60 days at 43.2 degrees C was 30 min, at 42.9 degrees C, 41 min, and at 42.3 degrees C, 92 min. In most rats with neurological symptoms after treatment, recovery from motor dysfunctions took place within about two weeks. Even severe neurological symptoms which did not lead to lethality recovered completely. At day 60 no neurological symptoms were observed.
Animals↗
The effects of anaesthetics on cisplatinum-induced toxicity at normal temperatures and during whole-body hyperthermia: the influence of NaCl concentration of the vehicle.
The effects of various anaesthetics, including a balanced combination of different anaesthetics (consisting of ketamine, xylazine, and acepromazine), Nembutal, and halothane anaesthesia on DDP-induced renal and intestinal toxicities at 37 degrees C and at 41.5 degrees C were studied using a F344 rat model. The combination anaesthesia decreased the DDP-induced lethality (LD50) and toxic side-effects as evidenced by decreased in BUN and diarrhoea at day 5, whereas nembutal anaesthesia increased DDP-induced toxic side-effects at 37 degrees C. The inhalation anaesthetic halothane had only minor influence on these DDP-induced toxicities. Increasing the NaCl concentration of the DDP vehicle from 0.9 to 1.8 per cent decreased the DDP-induced toxicity both in non-anaesthetized and anaesthetized animals. When applied simultaneously with DDP administration, whole-body hyperthermia (WBH; 120 min at 41.5 degrees C) increased the DDP-induced toxicity as indicated by the thermal enhancement ratio of between 2.1 and 2.7 for the LD50 values. With combined WBH + DDP treatment the effect of anaesthetics on DDP-induced toxicities was generally similar to that observed at 37 degrees C. The protective effects of the high NaCl (1.8 vs 0.9 per cent) concentration of the DDP vehicle, however, were minimal under hyperthermic conditions. The data suggest the need for caution in the use of DDP in combination with WBH.
Anesthetics↗
Effect of whole-body hyperthermia on pharmacokinetics and tissue distribution of doxorubicin.
The effect of whole-body hyperthermia (41.5 degrees C, 2 h) on doxorubicin (DOX) tissue distribution and plasma pharmacokinetics was examined in rats bearing a subcutaneous fibrosarcoma. Tumour response to the hyperthermia regimen alone was minimal, but the combination of heat with DOX (5.0 mg/kg, i.v.) enhanced tumour growth delay. The combined therapy, however, showed increased toxicity to normal tissue (especially renal and cardiac). Although DOX levels in spleen tissue were higher in rats exposed to hyperthermia than in control normothermic rats, both groups had comparable levels of drug in tumour, heart, kidney, and small intestine tissue at all time-points examined. Compared with normothermic animals, hyperthermia-treated rats showed decreased DOX in the mean area under the concentration-time curve (AUC) and decreased plasma DOX t1/2 but increased plasma drug clearance. These heat-mediated alterations in DOX pharmacokinetic parameters, however, do not account for the significant increases in thermochemotherapy-mediated cytotoxicities observed in tumour, and in normal renal and cardiac tissues.
Animals↗
Heat shock proteins (HSP-72 kd) in thermotolerant rat sciatic nerves.
Localized heating of the rat sciatic nerve over a length of 5 mm for 30 min at 43 degrees C resulted in the production of heat shock protein 72 kd in every nucleated cell and in the induction of thermotolerance in the heated area. HSP-72 kd was never detected in axons. Heat treatment (30 min, 45 degrees C) of thermotolerant nerves, 24 h after pretreatment, led to histopathological changes in the nerve, similar to those in non-thermotolerant nerves after a less strong treatment, i.e. heating for 30 min at 44 degrees C. Although axons did not contain HSPs after treatment at 43 degrees C, these structures tolerated treatment at 45 degrees C. Therefore we conclude that axons in the rat sciatic nerve are relatively heat-resistant and therefore we assume that axons do not need protection by HSPs; this is in contrast to endothelial cells and Schwann cells. Axons can be damaged indirectly as a consequence of vascular damage leading to ischaemia. Development of thermotolerance of the vasculature, ensuring a sufficient blood flow in the heated area, prevents this indirect damage.
Animals↗
Ultrastructural changes in the rat sciatic nerve after local hyperthermia.
The rat sciatic nerve was heated over a length of 5 mm for 30 min at 43, 44 or 45 degrees C. Morphological changes were not observed after heating at 43 degrees C. Treatment at 44 degrees C resulted in endoneurial oedema and mild vascular changes, such as contraction and vacuolization of endothelial cells and thickening of the media of the larger vessels. Within 1 week several demyelinated axons were observed. The first changes after heating at 45 degrees C included oedema, blood vessel occlusion and severe endothelial cell damage. Axonal changes, e.g. the accumulation of cell organelles, appeared 8 h after treatment; 24 h after treatment most axons and myelin sheaths showed degenerative changes. Absence of blood flow in the heated area of the nerve was shown 2 h after heating at 45 degrees C. We conclude that hyperthermic treatment directly affects endothelial cells and myelin sheaths in the rat sciatic nerve. Axons degenerate most probably as a consequence of ischaemia.
Animals↗
Effect of hyperthermia on the central nervous system: a review.
Experimental data show that nervous tissue is sensitive to heat. Animal data indicate that the maximum tolerated heat dose after local hyperthermia of the central nervous system (CNS) lies in the range of 40-60 min at 42-42 x 5 degrees C or 10-30 min at 43 degrees C. No conclusions concerning the heat sensitivity of nervous tissue can be derived from clinical studies using localized hyperthermia. The choice whether or not to exceed the critical heat dose, as derived from laboratory studies, in clinical practice is very much dependent on the clinical situation such as the anatomical site and volume of the tissue involved, and prior therapy. Data on clinical application of whole body hyperthermia (WBH) show that nervous tissue can withstand a slightly higher heat dose than after localized heating, which might be the result of developing thermal resistance during treatment. Expression of thermotolerance was observed in the spinal cord of laboratory animals. After WBH in man at a maximum between 40 and 43 degrees C for 6 h-30 min CNS complications were reported, but other complications seemed to be more life-threatening. Most studies indicate that impairment of the CNS after WBH was not due to direct heat injury to the brain or spinal cord, but was secondary as a result of physiological changes. Heat, at least if applied shortly after X-rays, enhances the response of nervous tissue to radiation. Neurotoxicity of chemotherapeutic drugs does not seem to be a limiting complication in hyperthermia if combined with chemotherapy, but only few data are available. The limited clinical experience shows that safe hyperthermic treatment of CNS malignancies or tumours located close to the CNS seems feasible under appropriate technical conditions with adequate thermometry and taking the sensitivity of the surrounding normal nervous tissue into account.
Animals↗
Chronic effect of whole-body hyperthermia combined simultaneously with cis-diamminedichloroplatinum (II) on normal tissue in rat.
Long-term effects of cisplatin (DDP) (6 mg/kg) alone at 37 degrees C and DDP (2 mg/kg) plus whole body hyperthermia 120 min at 41.5 degrees C) on DDP-mediated normal tissue toxicities were compared up to 12 months post-treatment using a F344 rat model. Acute renal damage, represented by an increase in blood urea nitrogen (BUN) at day 5 posttreatment, was significantly higher after DDP (6 mg/kg) alone at 37 degrees C than the increase in BUN after DDP (2 mg/kg) plus whole body hyperthermia. After recovery, BUN levels as a result of both treatments remained elevated. From 9 months onwards BUN levels as a result of the combined treatment gradually increased to values > 100 mg/dl. At 12 months, side toxicities as a result of the combined treatment were more severe than the side effects noted after DDP (6 mg/kg) alone at 37 degrees C. Red blood cell and hematocrit values were significantly reduced, whereas BUN was significantly increased. The results obtained with histological examination of the kidneys corresponded with the observed functional differences. Platinum levels in the kidney, however, were highest in the DDP (6 mg/kg) alone at 37 degrees C group. This observation does not explain why the chronic toxicity as a result of the combined modality treatment was more severe.
Animals↗
The influence of the oncogene N-ras on cell cycle delay in a human melanoma cell line with reduced radioresistance.
In a previous study we found that transfection of a human melanoma cell line with the oncogene N-ras led to increased radiosensitivity as measured by clonogenic assays. Since a shift in radiosensitivity is often correlated with altered G2/M delay, we investigated whether this was also the case in this oncogene containing melanoma cell line (IGRras). A human melanoma cell line, stably transfected with mutated N-ras, and its parental cell line transfected with the neomycin phosphotransferase gene only (IGRneo), were irradiated with 5 Gy and cell cycle distribution was measured at hourly time intervals by DNA staining with propidium iodide. Next, the effect of ionising radiation on the duration of the S-phase was determined by pulse labelling cells with BrdUrd before irradiation. Both cell lines showed a radiation induced G2/M delay, which was most prolonged for the ras transfected cell line. After 5 Gy, the S-phase duration was unaltered, although the shape of the relative movement (RM) curves was slightly different. No G1 delay was observed in either cell line. Ras transfection in a melanoma cell line leads to prolonged G2/M delay after radiotherapy. This prolongation is associated with increased radiosensitivity and not with radioresistance. These data throw doubt on the use of oncogene expression or G2/M delay as predictors of radiosensitivity.
Cell Cycle↗
Muscle wasting after radiotherapy in young and adult rats.
The impact of late muscular injury after radiotherapy on the well being of patients, particularly those treated at a relatively young age, is often underestimated. To extend the present knowledge, a detailed comparative study of the radiation response of skeletal muscles was performed. The hind limb of rats was irradiated at the age of 30-60 days (young), at approximately 200 days (adult) or at the age of >360 days (old), with single doses ranging from 15-60 Gy. Muscular wet weight, volume and tibia length was followed up to 12 months post-treatment. Radiation treatment resulted in muscular wasting, which was more severe at higher doses. The radiation response depended strongly on the age of the animal at the time of treatment. Radiation induced muscle wasting and stunted tibia growth were more prominent in young animals than in adult or in old rats. ED50 values based on normalized wet weight were 12.5 (11.5-13.6) Gy for young animals and 22.5 (21.8-23.3) Gy for adult animals. The gastrocnemius muscle of young animals appears to be more radiosensitive than the gastrocnemius muscle of adult or old animals. Furthermore, in young animals, severe wasting of the muscles may already occur after relative low radiation doses (single dose of 15 Gy).
Age Factors↗