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J Haveman

Publications and source records attributed to J Haveman.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1985

Thermal enhancement of the radiation damage in the mouse foot at different heat and radiation dose: influence of thermotolerance.

We studied the reaction of the mouse foot after combined X-irradiation and heat treatment. Acute reactions after heat differ from those after irradiation, however, after healing of the lesions, the same symptoms of deformity of the mouse foot remain. Prior heat treatment, 30 min at 43 degrees C, of the foot led to thermotolerance and this thermotolerance resulted in resistance to combined irradiation-heat treatments and hence to a decreased thermal enhancement of radiation effects. Resistance could be observed up to 168 h after prior heat treatment. The development of resistance to combined treatment at higher irradiation dose (15 or 20 Gy) and less severe heating was slower than at lower irradiation dose (10 Gy) and more severe heating. Thermal enhancement was confirmed to be dependent on the sequence of, and the interval between irradiation and heat treatment. When the mouse foot was made thermotolerant by prior heat treatment, thermal enhancement was always reduced, regardless of the sequence, when the combined heat and radiation treatments were given with an interval of less than 12 h. Thermotolerance led to an apparent decrease in the effective temperature employed in a combined treatment equivalent to approximately 1.0 degrees C, at temperatures above 43 degrees C in a 1 h heat treatment.

Animals↗
PubMed1984

A study of the effects of prior heat treatment on the skin reaction of mouse feet after heat alone or combined with X-rays: influence of misonidazole.

The skin of mouse feet was used to study the effects of hyperthermic treatment, either alone or combined with irradiation. The present experiments show that a priming heat treatment induces resistance both to a subsequent heat treatment and to a subsequent combined irradiation-heat treatment. The development of resistance to a combined irradiation-heat treatment after a priming heat treatment (30 min at 43 degrees C) was relatively slow (18-24 h) compared to development of resistance to a heat treatment without irradiation (6 h). Misonidazole, when administered prior to heat treatment only, did not influence the heat-induced skin reaction. However, when misonidazole was administered prior to combined irradiation-heat treatment, a slight but significant increase of the skin reaction was observed. Also, in combination with misonidazole resistance to combined treatment was observed by a priming heat treatment.

Animals↗
PubMed1984

The relevance of tumour pH to the treatment of malignant disease.

The wide range of tumour pH values that have been determined in human tumours is shown in Fig. 4. It can be seen that tumour pH values may be very low, or may fall in the same range as the values found in normal tissues. This means that pH-mediated modification of therapeutic effectiveness will be patient specific, rather than a general phenomenon. That the pH of the cellular environment might influence the effectiveness of various therapeutic agents is not a new idea. The data published in this field to date concerning such effects have been discussed extensively and are summarized in Table IV. Here we can see that low pH leads to decreased cell survival following treatment with hyperthermia, radiotherapy combined with hyperthermia, radiosensitizers and various chemotherapeutic agents. Conversely, low pH affords some protection against radiation and some drugs. Most of these data were, of necessity, derived from in vitro studies. In vivo studies are in most cases not feasible due to the difficulty of isolating the effect of one selected factor. Low tumour pH is, in vivo, generally assumed to be closely interlinked with tissue hypoxia and low blood-flow levels, each of which may individually influence the experimental outcome. Moreover, most of the aforementioned in vitro studies were conducted under well-oxygenated conditions. As previously mentioned, euoxic cells can, under certain conditions, maintain a pH gradient over the cell membrane. This collapses with the onset of hypoxia, leading to intracellular acidification. Low oxygen levels have been shown to be characteristic of many tumours. Within these limitations it is thus evident that tumour pH values could have far-reaching consequences for therapy. If the in vitro findings should prove to be relevant to the clinical situation various applications are possible. Pre-selection of patients less likely to respond to certain (toxic) chemotherapeutic agents, or conversely selection of agents that are more likely to be effective in the pH range of the tumour to be treated are two examples. Alternatively, the exploitation of low tumour pH values is a possibility. Agents that form or release toxic derivatives in areas of low pH, e.g., pH-sensitive liposomes, will work selectively in such areas. Tumour selective therapy may also be possible in patients with higher tumour pH values if the tumour pH can be lowered. This has been achieved experimentally by the administration of hyperthermia at temperatures above 42 degrees C, or by the administration of glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Influence of a prior heat treatment on the enhancement by hyperthermia of X-ray-induced inactivation of cultured mammalian cells.

The effect of prior heat treatment on thermal enhancement of radiation effects in treatments of cultured M8013S cells, derived from a transplantable murine mammary carcinoma, combining X-irradiation and 30 min at 43 degrees C up to 45 min at 45 degrees C in medium without serum have been studied. Prior heat treatment induces resistance to combined heat-irradiation treatments. A treatment of 30 min at 43 degrees C without prior heat treatment led to a thermal enhancement ratio of 2.2. With a prior 30 min at 43 degrees C treatment 6 hours before the combined heat-irradiation treatment, this ratio was decreased to 1.6. The relative resistance to combined treatments is very probably the result of the thermotolerant state of the cells induced by the prior heat treatment. The effects seem to be predominantly on the shoulder of the radiation survival curve. The resistance decays when the prior heat treatment is given longer than 24 hours before the combined heat-irradiation treatment. However, in the thermotolerant state large thermal enhancement ratios can be observed, this in spite of the resistance. A treatment of 45 min at 45 degrees C, 6 hours after a prior 30 min 43 degrees C treatment, led to an enhancement ratio of 6.0 both in medium with and without serum. Without prior heat treatment, the relative survival after 45 min at 45 degrees C is too low to enable determination of thermal enhancement of radiation effects. The sensitivity of the cells to a single heat treatment appeared to be dependent on nutritional conditions. Cells treated in medium without serum were more sensitive to heat. The sensitivity of preheated thermotolerant cells to a relatively short (up to 3 hours at 43 degrees C) heat treatment appeared to be rather independent of nutritional conditions, but the sensitivity of these cells to prolonged heat treatment (longer than 4 hours at 43 degrees C) was very dependent on the nutritional state. The presence of serum (and possibly other components in complete culture medium) made thermotolerant cells much more resistant to these long heat treatments. The present results may be important for clinical application of hyperthermia in combination with radiotherapy. They may provide guidelines concerning the intervals to be applied in fractionated treatments.

Adenocarcinoma↗