Hydrazobenzene oxidation by 2,6-dichlorophenol-indophenol in a photoreaction catalyzed by system I of photosynthesis. Hydrazine compounds as donors for photosystem II.
Explore the source record for details and available documents.
Chloroplasts↗
Biomedical subjects
J Haveman
Publications and source records attributed to J Haveman.
Absence of photosystem 2 in heterocysts of the blue-green alga Anabaena.
Explore the source record for details and available documents.
Cell Differentiation↗
Effect of indoleacetic acid on the growth of Rhizobium in culture.
Explore the source record for details and available documents.
Indoleacetic Acids↗
Wild-type p53-function is not required for hyperthermia-enhanced cytotoxicity of cisplatin.
The objective was to test the hypothesis that wild-type p53-function is required for the enhancement of the cytotoxicity of cis-diammine-dichloroplatinum(II) (cDDP) cytotoxicity by hyperthermia (HT). Human colorectal carcinoma cells (RKO) with wild-type p53-function and transfectants with HPV16-E6 or with a dominant negative mutant p53 were used. Cells were treated with HT (60 min at 41 degrees C, 43 degrees C, 45 degrees C: HT41, HT43, HT45). with various doses of cDDP alone or with a combined treatment, simultaneously applied. Survival was determined by clonogenic assays. Levels and localization of p53 were analysed with immunocytochemistry and Western blotting. The extent of HT41-enhanced cytotoxicity of cDDP was similar in all cell lines studied. Immunocytochemistry of wild-type p53 cells showed that p53 is transferred to the nucleus within 5 h after HT43, whilst after HT41 no significant effects were observed. Cell fractionation experiments of wild-type p53 cells showed that, immediately after HT43/HT45, nuclear p53-levels increased as compared to controls, but could not be extracted from the matrix. The extractability was restored 3-5 h after treatment. No significant differences in p53-levels were observed after HT41. These results indicate that, although HT43/HT45 might shortly inactivate p53-function, probably by protein aggregation to the nuclear matrix, the HT-enhanced cDDP-cytotoxicity does not depend on p53-function.
Antineoplastic Agents↗
Effects of hyperthermia on the rat bladder: a pre-clinical study on thermometry and functional damage after treatment.
The rat bladder was heated using a microwave applicator which was equipped with a system of circulating deionized water. The applicator was operated at 434 MHz and was placed at the ventral side with the rats in supine position. Temperatures in the bladder and adjacent were monitored using thermocouples with single or multiple sensors. One thermocouple located most centrally in the bladder served as reference. The rats were treated at intravesical reference temperature of 41, 42, 43, 44 and 45 degrees C for 1 h. The heating time to reach the reference temperature was approximately 5 min. Temperatures inside the bladder varied within 0.5 degrees C from the reference value, while the temperatures in the urethra were approximately 1.0 degrees C lower. At the left and the right side of the outer bladder wall, temperatures were approximately 0.5 degrees C lower than the reference value, while the temperature on the dorsal and ventral sides of the bladder wall were 1.0-1.5 degrees C lower. In the rectum, located in the treatment field, the temperature reached 39.1, 40.5, 42.4 and 42.5 degrees C after 1 h of hyperthermia at intravesical reference temperatures of 41, 42, 43, 44 and 45 degrees C, respectively. Body core temperature measured in the esophagus behind the pericardium never exceeded 40.0 degrees C. The capacity of the bladder was assessed after 1 h at 43, 44 and 45 degrees C at various intervals after heat treatment. In the sham treated control group and in the animals treated at 43 degrees C, no reduction in bladder capacity was observed. The treatment group where the bladder was kept at 44 degrees C for 1 h showed a clear reduction in bladder capacity at days 1 and 3 after hyperthermia. In the 45 degrees C treatment group, four out of seven rats died, this within a few days after treatment. The three surviving rats were tested for bladder capacity and all had a reduced capacity at days 3 and 7 post-treatment. Four weeks after 44 degrees C hyperthermia, all rats had recovered. After hyperthermia, depending on the heat-dose, an increase in blood urea nitrogen (BUN) was observed. After treatment at 42, 43 and 44 degrees C, peak values were observed after approximately 1 day (16 or 24 h) followed by recovery; after 42 degrees C, BUN levels were almost back to normal after 1 week; after 43 degrees C, the level was still twice as high as control levels; and after 44 degrees C, recovery of BUN levels to normal seemed slow, 1 week after treatment it was still five times as high as control. From these results, it is concluded that temperatures in the bladder below 44 degrees C are well tolerated. After 1 h at 44 degrees C, a transient decrease in bladder capacity was observed, as well as a high level of azotemia. After 1 h at 45 degrees C, a high mortality rate was observed. These observations agree with early clinical observations and may be used as guidelines for further clinical work.
Animals↗
Effectiveness of 2',2'difluorodeoxycytidine (Gemcitabine) combined with hyperthermia in rat R-1 rhabdomyosarcoma in vitro and in vivo.
PURPOSE: To investigate the schedule-dependency of 2',2'difluorodeoxycytidine (dFdC, Gemcitabine) combined with hyperthermia (HT), in vitro as well as in vivo. MATERIALS AND METHODS: Rat R-1 rhabdomyosarcoma cells were treated with various concentrations of dFdC for 70 min, 4 h and 24 h. After various time intervals HT (60 min at 43 degrees C) was applied. Cell survival was determined by clonogenic assays. Female Wag/Rij rats bearing R-1 tumours on the hind limbs were treated with dFdC (20 mg/kg), with locally applied HT (60 min at 43 degrees C) or with a combined treatment using different time intervals (0, 24 and 48 h). Tumour growth delay (TGD) and normal tissue toxicity were assessed. RESULTS: With dFdC alone, significant cytotoxicity was observed after a 24 h-exposure. Except for the 24 h-exposure, HT reduced the cytotoxicity of dFdC in simultaneous applications. An enhanced cytotoxic effect was found when HT was applied 20 h after a 4 h-incubation with dFdC. In vivo, HT applied 48 h after dFdC-administration resulted in potentiation of the effect of dFdC with respect to TGD without an increase in toxicity. CONCLUSIONS: The efficacy of dFdC combined with HT is schedule-dependent both in vitro and in vivo. The addition of HT enhances the effectiveness of dFdC in the R-1 tumour model.
Animals↗
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↗
Histopathological changes in the spinal cord after 434 MHz microwave hyperthermia in the cervical region of the rat.
The time-course of thermal damage to the spinal cord was studied after hyperthermia of the cervical region in the rat. Local 434 MHz microwave heating of the spinal cord (cervical 5-thoracic 2) was obtained by using a ring-shaped applicator. Heat treatment at 42.9 degrees C (+/- 0.4 degrees C) for 38 min resulted in neurological symptoms, ranging from uncoordinated use of the forelegs to paralysis and death in 90 per cent (28/31) of the animals. Histological sectioning of the treated part of the spinal cord was performed immediately, 4, 24 h and 3, 7, 14 and 28 days after hyperthermia. Immediately and 4 h after treatment, neurons in the grey matter of the cord were affected and vacuolization was observed in the white matter. In animals with paralysis 1 day after treatment, we noticed neuronal degeneration, myelin pallor and sometimes haemorrhagic foci in white and grey matter. As a reaction to the thermal injury, gliosis was observed and invasion of macrophages and lymphocytes (day 3-14). Animals which had severe neurological symptoms at day 1 after hyperthermia, but had recovered completely 28 days after treatment, showed focal scar formation and demyelination in the spinal cord. The observed neurological complications correlated well with the localization of the observed histopathological changes in the cervical spinal cord.
Animals↗
What is a safe heat dose which can be applied to normal brain tissue?
Explore the source record for details and available documents.
Animals↗
Thermotolerance of the spinal cord after fractionated hyperthermia applied to the rat in the cervical region.
The effects of heat treatment at 42.9 +/- 0.4 degrees C for 30-90 min of rat cervical spinal cord (cervical 5-thoracic 2) were investigated in animals which had received a priming treatment at 42.3 +/- 0.4 degrees for 60 min in the same region 24 hours before. Hyperthermia to the cervical region in the rat was applied by a coaxial double ring radiator, operating at a frequency of 434 MHz. The test heat treatment led to neurological complications, ranging from unco-ordinated use of the forelegs to paralysis of both forelegs. Death was observed, presumably as a result of respiratory paralysis. The animals that received the priming heat treatment were more resistant to heat injury than those without priming. The LD50, 60 days, for animals without and with priming treatment was respectively at 41 +/- 2 min 42.9 degrees C and at 88 +/- 7 min 42.9 degrees C. The TTR calculated from the LD50, 60 days, data is 2.1 +/- 0.2. Almost all animals, without priming, that did not die as a result of the treatment, recovered in the period from day 1 to day 60 after hyperthermia. Animals that had received a priming exposure were less able to recover from neurological symptoms induced by the test heat treatment. For this reason the induced resistance to thermal injury after priming exposure was more pronounced in the data on lethality than on neurological symptoms. Spinal cord histology from animals that did not recover from neurological symptoms showed extensive non-vascular damage to both gray and white matter.
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↗
Cytokine production after whole body and localized hyperthermia.
The levels of TNF, IL-1 and IL-6 in circulating blood female WAG/Ry rats were assessed in relation to treatment with localized hyperthermia of the right hind leg or with whole-body hyperthermia (WBH). After a localized treatment for 30 min at 43 or 44 degrees C no detectable increase in levels of IL-6 or TNF was obtained. Hyperthermia for 30 min at 45 degrees C led to an elevated level of IL-6 of 19.4 +/- 5.2 U/ml above the control level of 24 h after treatment. Levels of IL-1 were never higher than those in control animals that received only anaesthesia. Anaesthesia induced a peak level of approximately 131 U/ml IL-1 6 h after treatment. Serum levels of IL-1 and IL-6 are enhanced after WBH. IL-1 reaches a peak level already during WBH about 15 after reaching 41.5 degrees C. IL-6 levels were not enhanced during WBH but 1 h after WBH a clear peak was observed. Anaesthesia with sham WBH did not lead to enhanced IL-6 levels but enhanced IL-1 levels were clearly detected. We did not detect TNF in any sample after WBH. It is concluded from the present results that IL-6 is not induced by a 'standard' treatment of localized hyperthermia as used in oncotherapy (i.e. 60 min at 43 degrees C) to such a high level locally that this is reflected in increased levels in circulating blood. WBH at clinically relevant temperatures leads to enhanced levels of IL-1 and IL-6. The difference in IL-6 response after WBH or localized hyperthermia probably is related to the fact that in WBH also the bone marrow is treated. This may lead to stimulation of this important stem cell compartment of the peripheral blood. The sequence of appearance of IL-1 and IL-6 after hyperthermia is akin to the sequence in an inflammatory response. However, the experiments with sham treatment show that IL-1 may appear in the circulating blood not followed by IL-6. These results indicate that enhanced IL-1 levels may reflect a stress reaction of the animal related to the (sham) treatment. Enhanced levels of IL-1 after WBH correlate with enhanced levels of ACTH in the circulating blood.
Animals↗
Lack of thermal enhancement for taxanes in vitro.
The taxanes represent a new class of clinical chemotherapeutic agents. A series of in vitro studies were independently of each other initiated in two different institutes (Amsterdam and Madison) to test the hypothesis that hyperthermia might enhance the cytotoxicity of taxanes. Clonogenic capacity experiments (Amsterdam) included the exposure of R1- and SW 1573-cells to 1, 4, or 24 h of paclitaxel with heat 43 degrees C x 60 min in the last hour of drug treatment or at 24, 48 as well as 72 h post drug treatment. Survival assay experiments (Madison) included the exposure of L-929-cells to paclitaxel and docetaxel for 24 h with heat 41.8 degrees C x 60 min the first or last hour of drug treatment as well as 24 and 48 h post treatment. No thermal enhancement of cytotoxicity for the taxanes was observed in these human and murine cell lines, with congruent data in both institutes. In addition, high performance liquid chromatography studies at 41.8 degrees C and 43 degrees C demonstrated paclitaxel and docetaxel were heat stable.
Animals↗
Comment on response to paper by d'Oleire et al.
Explore the source record for details and available documents.
Animals↗
Hyperthermia may decrease the development of telangiectasia after radiotherapy.
CASE REPORT: A patient with recurrent breast cancer was reirradiated twice on adjacent fields with a time interval of 9 months. The first time she was treated with reirradiation alone, the second time with reirradiation plus hyperthermia. The reirradiation schedule for both fields was 8 x 4 Gy in 4 weeks. Both fields overlapped partly with the field of postoperative radiotherapy, which was applied 57 and 66 months earlier to a total dose of 40.5 Gy. RESULTS: During the 52 to 61 months follow-up, a remarkable difference in telangiectasia development, between the parts of the reirradiation fields overlapping with the primary radiotherapy field, became apparent. Telangiectasia was observed 9 months after treatment with reirradiation alone and progressed to confluent in 47 months after treatment. In the reirradiation plus hyperthermia area, the maximum observed telangiectasia was slight until 52 months after treatment. DISCUSSION: The difference in the development of telangiectasia between these fields cannot be explained by differences in any of the known radiation treatment related prognostic factors. A protective effect by hyperthermia has been suggested by Haveman and coworkers, who have shown experimentally that heat treatment leads to enhanced proliferation of endothelial cells, thereby inducing a fast repopulation and replacement of X-ray damaged cells. CONCLUSION: This difference in telangiectasia formation is an interesting observation. Whether such a protective effect of hyperthermia is of general relevance has to become clear from more extensive clinical studies.
Breast Neoplasms↗
TNF, IL-1 and IL-6 in circulating blood after total-body and localized irradiation in rats.
The levels of TNF, IL-1 and IL-6 in circulating blood of female WAG/Rij rats were assessed both after total-body irradiation (TBI) and localized irradiation of the right hind leg. The results show that enhanced levels of IL-1 in the circulation reflect a stress situation presumably resulting from handling and halothane anesthesia of the animal. Neither localized irradiation nor TBI resulted in further enhanced levels of IL-1. Both TBI and localized irradiation, lead to a small but significant increase in IL-6 levels in serum from circulating blood. After TBI this increase dissipated rapidly, 24 h after TBI increased levels are not found. After localized irradiation IL-6 levels remain elevated for a longer period. Still two weeks after irradiation, the longest time investigated, increased levels were observed. We did not observe increased TNF levels after localized irradiation or after TBI.
Animals↗