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Biomedical subjects

J Haveman

Publications and source records attributed to J Haveman.

At least 37 records · Page 2Linked to original sources
PubMed1991

Effects of hyperthermia applied to previously irradiated cervical spinal cord in the rat.

Rat cervical spinal cord was X-ray irradiated at doses of 15, 18, 20 and 26 Gy. Ninety days later, approximately the same part of the spinal cord was heated at 42.3 +/- 0.4 degrees C for 50, 60, 75 or 90 min by means of a 434 MHz microwave applicator. After treatment, animals were observed over a period of 18 months for expression of neurological complications. These complications could either be the result of the heat or of the radiation treatment. The time course showed three distinct peaks in the incidence of neurological symptoms. The first peak was due to the acute response to hyperthermia. The ED50 value for neurological complications one day after treatment at 42.3 +/- 0.4 degrees C was 74 +/- 2 min. Previous X-ray irradiation of the spinal cord with 18, 20 and 26 Gy reduced the ED50 to 57 +/- 7, 65 +/- 4 and 55 +/- 5 min (12-26% of control), respectively. Recovery from heat-induced neurological complications was diminished in previously irradiated animals. The second peak (150-300 days after X-rays) concerned the expression of "early delayed" radiation damage. Hyperthermia given 90 days after irradiation did not influence either the percentage of animals with paralysis or the latent period. Neurological symptoms developing after day 300 were due to the "late delayed" radiation response. No significant difference was observed in the data on paralysis induced by radiation alone or radiation followed by heat. The late radiation-induced minor neurological symptoms were, however, influenced by retreatment with heat.

Animals↗
PubMed1991

Induction of thermal tolerance of rat sciatic nerve by mild hyperthermia.

A 5 mm segment of the rat sciatic nerve was treated at 38 or 43 degrees C for 30 min using a brass thermode. This pretreatment was followed by a test heat treatment at 45 degrees C. Different intervals between the pretreatment and test treatment were studied. The effect of fractionated hyperthermia on the motor function of rat sciatic nerve was evaluated using a functional assay, the toe-spreading test. Both pretreatments led to thermal resistance of the nerve, which was maximal 24 h after the pretreatment. Thermal resistance, induced at 38 degrees C, did not show any decay over a period of 6 weeks. Thermal resistance, induced at 43 degrees C, decayed slowly, but after a 6-week interval between priming and test heat treatment thermal resistance was still observed. As the resistance induced by a mild heat pretreatment is transient, we considered this to be thermotolerance. We accounted for the thermal resistance induced by the 38 degrees C pretreatment in the calculation of the thermal tolerance ratio (TTR) after mild heat treatment at 43 degrees C. Maximal thermal tolerance was observed 24 h after mild heat with a TTR of 3.4 +/- 0.6. The TTR after a 6-week interval had declined to 1.4 +/- 0.3.

Acclimatization↗
PubMed1991

Enhancement by hyperthermia of the 'early delayed' and 'late delayed' radiation response of the rat cervical spinal cord.

The cervical spinal cord (C5-T5) of female Wistar WU rats was irradiated with 250 kV X-rays (15-32 Gy). Heat was applied at approximately the same site 7 +/- 1 min after X-rays. 'Early delayed' paralysis of the forelegs was observed 5-10 months after treatment. The ED50 (+/- SE) after single-dose irradiation alone was 25.8 +/- 0.4 Gy. 'Late delayed' paralysis and paresis were observed 11-21 months after irradiation with an ED50 (X-rays alone) of 22.7 +/- 0.6 Gy. The data for late paralysis, late paresis and minor neurological symptoms were pooled resulting in an ED50 (+/- SE) of 20.6 +/- 0.7 Gy. Hyperthermia enhanced the radiation response. Thermal enhancement ratios (TER) in the 'early delayed' response after a 30 min treatment with 41.1 +/- 0.4 degrees C 42.1 +/- 0.4 degrees C and 42.9 +/- 0.4 degrees C were 1.07 +/- 0.08, 1.17 +/- 0.08 and 1.12 +/- 0.04, respectively. For the 'late delayed' radiation response concerning paralysis and paresis the TER after 30 min at 41.1 degrees C and 42.1 degrees C were 1.25 +/- 0.10 and 1.31 +/- 0.07, respectively. The latent period for paralysis was not significantly affected. Pathological examination of the spinal cord after combined treatment of X-rays and hyperthermia showed focal demyelination with white matter necrosis and vascular injury in animals as an indication of 'early delayed' and 'late delayed' paralysis, respectively. This was not different from histopathological changes observed after irradiation alone.

Animals↗
PubMed1991

Hyperthermia promotes the incidence of tumours following X-irradiation of the rat cervical cord region.

The cervical region of the rat, including the spinal cord (cervical 5-thoracic 2) was irradiated with single doses of 15-32 Gy 250 kV X-rays. Hyperthermia, at temperatures of 42-, 43- and 44 +/- 0.1 degrees C for 30 min was applied to the cervical vertebral column and immediate adjacent tissues for 5-10 min or 7 h after X-irradiation. Over a period of 18-21 months, animals were followed up to monitor neurological complications occurring as a result of damage to the spinal cord (Sminia et al. 1991). We also noted the development of neoplasms either inside or outside the cervical region. The data on tumour incidence were analysed retrospectively using the actuarial method. Although hyperthermia alone was not carcinogenic, it led to a significant increase of radiation-induced tumours. This increase of radiation carcinogenesis was observed both with hyperthermia applied 5-10 min after X-rays and with an interval of 7 h between X-rays and heat. Cancer induction was highest after the lower radiation doses (16 Gy) combined with high heat doses (30 min 44 degrees C). The latent period for induction of tumours by X-rays was 472 +/- 19 days (mean +/- SEM; n = 24). Latency was significantly shortened by hyperthermia to 404 +/- 34 days (n = 22) if applied 5-10 min after X-rays and to 348 +/- 6 days (n = 33) with an interval of 7 h. Histology revealed that 86% (38/44) of the examined tumours found inside the volume treated with hyperthermia and irradiation were sarcomas. The percentage of animals with a tumour outside the treated volume was almost the same for all treatment groups. Most of these tumours were of the mammary gland type.

Animals↗
PubMed1990

Histopathological changes in the skin and subcutaneous tissues of mouse legs after treatment with hyperthermia.

The right hind legs of mice wee heated in a waterbath at 44 degrees C. The animals were killed at various time intervals after exposure. Tissue damage was studied histologically. After 15 min exposure light and reversible changes were seen including oedema and some neutrophilic inflammatory infiltration immediately after treatment. After 30 min exposure an extensive inflammatory infiltrate and strong oedema were seen during the first days after treatment. Adjacent to areas in the skin with strong oedema extensive muscular necrosis was observed. The muscular tissue regenerated almost completely in three weeks. After 60 min heating the histological picture was dominated by massive necrosis of muscle, subcutaneous fat tissue and skin during the first week after treatment followed by local ulceration. From about the 7th day after treatment regeneration of the epithelium started and granulation tissue could be observed in the margin of the ulceration. Healing of the skin was completed at about day 21 after treatment. Our results indicate that heat induced tissue damage in some tissues is due to a direct effect on the cells composing the tissue (e.g., fat cells in subcutaneous fat) but that, in most other tissues (e.g., muscle and skin) it is a consequence of damage to the vasculature.

Adipose Tissue↗
PubMed1990

Incidence of tumours in the cervical region of the rat after treatment with radiation and hyperthermia.

The incidence of tumours in the irradiated cervical region in female Wistar (WU) rats after retreatment of part of the volume with hyperthermia was examined retrospectively. The cervical spinal cord (cervical 5-thoracic 2) was irradiated with a single dose of 15, 18 or 20 Gy. Ninety days thereafter, the cervical region was heated by means of a microwave applicator at a maximum temperature of 43 degrees C for 50-90 min measured at the vertebral column. Over a period of 18 months after treatment, animals were regularly observed. Neurological complications and the development of neoplasms were noted. From the 354 animals included in the study, 82 animals developed a tumour. Hyperthermia alone was not carcinogenic, but enhanced the carcinogenesis induced by radiation. The percentage of animals that developed a tumour inside the volume treated with hyperthermia 90 days after irradiation was significantly higher relative to radiation alone (33 +/- 5 per cent versus 4 +/- 2 per cent, P less than 0.001). The duration of the latent period before appearance of these tumours was not affected (355 +/- 18 days versus 425 +/- 54 days). No significant differences in the percentage of animals that developed a tumour at another site were observed between different treatment groups. Histology revealed that 88 per cent (14/16) of the examined tumours found inside the treated volume after hyperthermia and irradiation were soft tissue rhabdomyosarcomas. Outside the treated volume, most tumours were tumours of the mammary gland.

Animals↗
PubMed1989

Effect of N-acetylcysteine on the antiproliferative action of X-rays or bleomycin in cultured human lung tumor cells.

N-Acetylcysteine is currently being considered as a possible selective protector against pulmonary toxicity resulting from X-rays or chemotherapeutic treatment, but its clinical application awaits evidence that it does not interfere with the efficient killing of tumor cells. The capacity of N-acetylcysteine to protect against the antitumor activity of X-rays and of bleomycin was evaluated in a clonogenic cell-survival assay using SW-1573 human squamous lung carcinoma cells as a tumor model. Using the highest non-toxic dose of N-acetylcysteine (incubation for 2 days in the continuous presence of 10 mM) no effect on clonogenic cell killing by X-rays or bleomycin treatment could be detected, even though a twofold enhancement of endogenous glutathione was effectuated. Our data thus indicate that clinically relevant concentrations of N-acetylcysteine are incapable of protecting tumor cells against clonogenic killing by X-rays and by bleomycin.

Acetylcysteine↗
PubMed1989

The relationship between treatment duration and temperature for hyperthermia induced lethality of cultured murine cells. Influence of medium conditions.

The heat sensitivity and the time-temperature relationship of non-tolerant and thermotolerant M8013 cells treated at different pHs in either culture medium (including serum) or Hanks' salts solution (HBSS) were compared. The cells were growing asynchronously. Arrhenius plots for non-tolerant cells heated in culture medium pH 7.35 showed two linear parts below and above the transition temperature (Ttrans). The inactivation energies below and above Ttrans were respectively 2980 and 490 kJ/mole. With thermotolerant cells under the same conditions the inactivation energy was approximately constant over the range 42-46 degrees C at 890 kJ/mole. The cells were more sensitive to heat treatment at low pH or in HBSS. Moreover, it appeared that the expression of thermotolerance was strongly dependent on medium conditions: the thermotolerance ratio (TTR, ratio between slopes of survival curves of thermotolerant and normal cells) was much lower at low pH or in cells heated in HBSS. Generally a high TTR observed in experiment with fractioned hyperthermia at temperatures above Ttrans correlated fairly well with a high inactivation energy below Ttrans from the Arrhenius plot derived from data from experiments with the same cells that were not made thermotolerant before treatment.

Animals↗
PubMed1988

Cell proliferation in the murine epidermis and subcutaneous vascular endothelium after hyperthermia.

The skin of mouse legs was exposed to 44 degrees C hyperthermia using a thermostatically controlled waterbath. Treatment at 44 degrees C, for 15 or 30 min, led to oedema in the dermis immediately after treatment and to an infiltration by neutrophils within 7 h. The oedema disappeared in 2 days. Treatment for 60 min at 44 degrees C led to subepidermal blistering and as a result of this a considerable area of the tissue became necrotic 4 days after treatment. A repair reaction followed, and 3 weeks after heating for 60 min at 44 degrees C the epithelium was again completely or almost completely covering the underlying tissue. Shortly (7 h) after 15 or 30 min at 44 degrees C an increase was observed in the number of basal cells in the epithelium incorporating [3H]thymidine. This increase declined slowly with time: 3 weeks after treatment the number of labelled basal cells was not significantly different from that in untreated skin. Shortly after 60 min at 44 degrees C some basal cells of the epidermis still incorporated [3H]thymidine. The labelling index dropped to near-zero at day 2 after 60 min at 44 degrees C. Thereafter repopulation started and in the areas next to the granulation tissue the labelling index of basal cells reached values close to 100 per cent, 2 or 3 weeks after treatment. Treatment for 15 min at 44 degrees C did not lead to a stimulation of the proliferation of subcutaneous endothelial cells. Both 30 min and 60 min at 44 degrees C led to a greatly enhanced proportion of labelled subcutaneous endothelial cells after 2 days and 4 weeks, respectively (labelling index between 35 and 40 per cent). After this peak value the labelling index declined rapidly. However, in granulation tissue it remained high for about 10 days after the peak on day 4. The stimulated proliferation of subcutaneous endothelial cells after heating for 30 and 60 min at 44 degrees C correlated well with the finding that these heat treatments, given after or shortly before X-irradiation, led to a greatly reduced (X-ray-induced) tumour bed effect.

Animals↗
PubMed1988

Effects of local hyperthermia on the motor function of the rat sciatic nerve.

The effect of local heat treatment of the sciatic nerve was assessed using the toe-spreading test, which mainly assesses the motor function of the sciatic nerve. A 5 mm long segment of the nerve was heated at temperatures from 42.0 to 45.0 degrees C in vivo using a brass thermode. Hyperthermia led to a decrease in spreading of the toes. Recovery from functional loss took place in all cases, and this recovery was completed in 4 weeks. A 50 per cent functional loss in 50 per cent of the treated animals was observed after 58, 32 and 12 min of heating at 43.0, 44.0 and 45.0 degrees C respectively.

Animals↗
PubMed1987

The effect of previous treatment on the response of mouse feet to irradiation and hyperthermia.

The response of mouse feet to irradiation and heat was studied 90 days after a first treatment with X-rays, hyperthermia or both. Residual damage after a single dose of 20-30 Gy enhanced both the acute reaction and "late" deformity following a second treatment with radiation or hyperthermia. There was often a larger "memory" of the first radiation treatment for late deformity compared with the acute skin response, especially in the case of retreatment by hyperthermia. Prior treatment of the foot with a moderate heat dose (60 min at 44 degrees C), which by itself did not lead to deformity, had only a small effect on the response to retreatment with irradiation or heat, both with respect to the acute and "late" response. Residual damage after more severe hyperthermia (90 min at 44 degrees C) obscured the evaluation of deformity after a second treatment with radiation or hyperthermia. Feet treated with irradiation followed immediately or after 3 days by heat, show a larger "memory" when retreated with hyperthermia than with irradiation, both with regard to the acute and "late" response. Experiments using misonidazole indicated that the oxygenation status of previously treated skin (pretreatment not leading to deformity) had not changed significantly.

Animals↗
PubMed1987

Thermal radiosensitization and thermotolerance in cultured cells from a murine mammary carcinoma.

Cultured murine mammary carcinoma cells M8013 could be made thermotolerant by a priming heat treatment, 30 min at 43 degrees C, applied 5 h prior to subsequent heat treatment. The sensitivity of non-tolerant and thermotolerant cells to either radiation or heat combined with radiation was investigated. Analysis of survival curves with respect to D0 and N showed that thermotolerance had no influence on the radiation sensitivity of the cells. Thermal enhancement of radiation effects (in combined heat/irradiation treatments) was however reduced as a result of thermotolerance. When thermal enhancement ratios were (D0) plotted as a function of the cell killing effects of heat treatment alone, thermotolerance did not seem to have any influence. This latter observation suggests that thermotolerance modifies the effectiveness of the heat treatment for heat-induced cell lethality and radiosensitization equally. Comparison of our in vitro results with several in vivo data on normal tissues suggest that the reduction in 'effective' treatment temperature which has been observed in the in vivo studies as a result of thermotolerance may be explained by equal modification of the effects of heat by thermotolerance both for its direct effects and the radiosensitization.

Acclimatization↗
PubMed1987

Influence of prior heat treatment on the effects of heat alone or combined with X-rays on mouse stromal tissue.

The tumour bed effect assay was used to study the sensitivity of mouse stromal tissue to heat applied alone or combined with irradiation. Prior heat treatment, 30 min at 43 degrees C, of the tumour bed led to thermotolerance. After priming, thermotolerance developed fully within 24 h and it had disappeared completely after about 10 days. The kinetics of development and decay of thermotolerance in this slowly dividing tissue is similar to that which we had observed previously in skin. When decay rates of several normal tissues with different proliferation characteristics are compared, it is obvious that there is not a clear relationship between proliferation rate of the presumed target cells in the tissue and thermotolerance decay rate.

Acclimatization↗
PubMed1986

Chemically induced resistance to heat treatment and stress protein synthesis in cultured mammalian cells.

Short exposure (1-2 h) of cultured cells, derived from a transplantable murine mammary carcinoma, to sodium arsenite, 2,4-dinitrophenol (DNP), carbonylcyanide-3-chlorophenylhydrazone (CCP) or disulfiram, induced resistance to a subsequent heat treatment, similar to heat-induced thermotolerance. Optimum resistance to a test heat treatment of 45 min at 45 degrees C after sodium arsenite exposure was obtained at a concentration of 300 microM, after DNP exposure at 3mM, after CCP at 300 microM and after disulfiram exposure in the range 1-30 microM. Exposure of cells to CCP, sodium arsenite or disulfiram led to enhanced synthesis of some proteins with the same molecular weight as 'heat shock' proteins. The pattern of enhanced synthesis of these proteins was agent specific. We could not detect significantly enhanced synthesis of the proteins after DNP using one-dimensional gel electrophoresis. These results suggest that enhanced stress protein synthesis is not a prerequisite for the development of thermal resistance.

2,4-Dinitrophenol↗
PubMed1986

Effects of hyperthermia and X-irradiation on mouse stromal tissue.

The sensitivity of normal stroma to heat, irradiation and heat combined with irradiation has been studied using the tumour bed effect (TBE) assay. Irradiation before implantation led to a TBE. This TBE was dose dependent below 15 Gy, the TBE remaining relatively constant above 15 Gy. The interval (0-90 days) between irradiation and tumour implantation did not influence the magnitude of the TBE. Hyperthermia with large heat doses (45-60 min at 44 degrees C) before implantation may lead to a TBE. The interval between hyperthermia and tumour implantation proved to be very important. Our results show that the recovery from heat-induced stromal damage is very rapid. When the interval between hyperthermia and tumour implantation is 10 days or longer, no TBE could be observed. Irradiation combined with large heat doses (30-60 min at 44 degrees C) decreased the radiation-induced TBE. However, the combination of irradiation with mild heat treatments (15 min at 44 degrees C) could lead to a larger TBE than after irradiation alone. When hyperthermia was given prior to irradiation, the interval between heat and irradiation proved to be very important. With large intervals (21 days or longer) the TBE values were about the same as with irradiation alone. When heat was given after irradiation it always reduced the irradiation-induced TBE.

Animals↗
PubMed1985

Influence of thorax irradiation on the survival of mice with spontaneous or artificial lung metastases from a transplantable mammary adenocarcinoma.

The effect of thorax irradiation on lung metastases, either occurring spontaneously from a primary mammary adenocarcinoma (M8013X) transplanted on the leg or artificially induced by intravenous injection of tumor cells was studied. Increasing the interval between the moment at which lung metastases are supposed to originate and the thorax irradiation resulted in a rapid decrease of the effectiveness of this treatment in preventing the development of lung metastases. Early treatment of the mice not only resulted in a considerable number of animals that were cured, but also in a significant decrease in the number of tumor localizations in the lung of those animals still developing metastases. Thorax irradiation performed later was much less effective; at autopsy the lung showed a large number of small metastases. Increasing the radiation dose led to an increased number of cures; however, an increased number of mice dying of lethal lung damage was also observed. Irradiation of the lungs of mice with 5 or 10 Gy, 24 hours, 7 days or 14 days prior to i.v. injection with tumor cells, did not significantly increase the number of mice with lung metastases. Immunological resistance against the tumor played a role in our experiments with both spontaneous and artificial lung metastases.

Adenocarcinoma↗