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Biomedical subjects

J Haveman

Publications and source records attributed to J Haveman.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1983

Influence of pH and thermotolerance on the enhancement of X-ray induced inactivation of cultured mammalian cells by hyperthermia.

The influence of pH and thermotolerance on thermal enhancement of radiation effects have been studied with M8013 cells, derived from a transplantable murine mammary carcinoma. The effect of combined heat-irradiation treatment of cells at different pH of the medium clearly shows an influence of the pH. Thermal enhancement of the effectiveness of radiation is relatively strong below pH 7.0 and above pH 7.75. In the physiological range pH 6.7-7.4 the influence of pH is not very large. This implies that combination of hyperthermia and radiotherapy in cancer treatment would not give much therapeutic advantage from low pH which is often observed in solid tumours as this low pH is rarely below pH 6.7. Sensitization of cells to the effects of heat treatment alone at a low pH of the cellular medium is greatly decreased when thermotolerance is induced in the cells by a prior heat treatment 4-6 hours before the final treatment. When the cells are in the thermotolerant state, induced by a prior heat treatment, not only resistance to heat treatment, but also resistance to combined heat-irradiation treatment is observed. The degree of this latter resistance is independent of the pH of the cellular medium during the combined heat-irradiation treatment. In spite of the resistance, strong thermal enhancement of radiation effects can be observed when cells are treated in the thermotolerant state by a strong heat treatment. Without thermotolerance such a strong heat treatment, whether combined with irradiation or not, caused so much effect that it was impossible to determine relative cellular survival. The enhancement of radiation effects by a strong heat treatment with cells in the thermotolerant state is largely independent of the pH of the cellular medium.

Adaptation, Physiological↗
PubMed1983

The response of previously irradiated mouse skin to heat alone or combined with irradiation: influence of thermotolerance.

The skin of the mouse foot was used to study the effects of previous irradiation on the response to hyperthermia (44 degrees C), to irradiation, or to irradiation combined with hyperthermia (43 degrees C or 44 degrees C). Hyperthermia was applied by immersing the mouse foot into a hot waterbath and irradiation was performed using a 250 kV X-ray generator. Previous irradiation of the feet of mice 90 days before, with 20 Gy, increased the subsequent response to heat alone, or when combined with irradiation, as well as to irradiation alone. It had little effect on the thermal enhancement ratio's for both acute and late skin reactions. Memory of the previous irradiation treatment could be masked when the temperature of the subsequent heat treatment alone, or when combined with irradiation, was 44 degrees C. A priming heat treatment induced resistance both to a subsequent heat treatment and to a subsequent combined irradiation-heat treatment in normal skin as well in previously irradiated skin. This 'resistance' is probably mainly the result of thermotolerance induced in cells in the skin by the priming heat treatment. In thermotolerant skin a 'memory' of the previous irradiation was always evident when the reaction after heat alone or heat combined with irradiation was measured. When the late skin reaction was considered, a larger 'memory' of the previous irradiation treatment was always evident, compared to the acute skin reaction: the 'remembered' dose in the late skin reaction was about two times the 'remembered dose' in the acute skin reaction.

Acclimatization↗
PubMed1982

Effect of hyperthermia and misonidazole on the radiosensitivity of a transplantable murine tumor: influence of factors modifying the fraction of hypoxic cells.

Hypoxia has been demonstrated to play an important role in the effect of hyperthermia on tumors. We have studied the influence of different factors modifying the oxygenation status of a transplantable murine mammary adenocarcinoma (tumor volume and pentobarbital sodium anesthesia). The effect of hyperthermia alone on the tumor is not significantly influenced by the change in oxygenation status during the growth of the tumor. Also, the large increase of the acutely hypoxic cell fraction, as a result of anesthesia, does not change the effect of hyperthermia alone. In the combined irradiation-heat treatment there is a clear influence of the chronically hypoxic cell fraction on the response to hyperthermia: an increase in tumor size, resulting in a larger hypoxic cell fraction, leads to an increase in thermal enhancement ratio. However, the increased acutely hypoxic cell fraction, resulting from anesthesia, did not lead to an increase in thermal enhancement ratio; in fact the enhancement ratio apparently decreased. In spite of the fact that hyperthermia was applied immediately after irradiation no potentiation of radiation effects was found. The thermal enhancement of the radiation response was never larger than the enhancement as a result of misonidazole. All thermal enhancement could be explained by effects of heat on the chronically hypoxic cell fraction. Misonidazole had no effect on the response of tumors to heat alone, but greatly enhanced the effect of heat combined with irradiation. Anesthesia of the animals did not influence these effects of misonidazole.

Anesthesia↗
PubMed1982

Effects of irradiation by single or multiple fractions per day on transplantable murine mammary carcinoma.

Effects of different fractionation schedules of irradiation were studied in an experimental mammary adenocarcinoma transplanted in the back of mice. The number of fractions per day varied from one to three, keeping the daily dose constant. It was found that an increase of the number of fractions per day did not necessarily lead to a decrease in the tumour response, as might be expected for the same total dose. At a twelve-day overall time, three fractions per day did not give such a good result as one fraction per day, but at a nineteen-day overall time three fractions per day were about as good as one fraction per day; and below 45 Gy total dose, the result with three fractions per day even seemed to be better. The effects of actinomycin D administered during the irradiation treatment show that schedules with three fractions per day possibly take better advantage of repair of sublethal and potentially lethal damage than schedules with one fraction per day. Administration of misonidazole during the irradiation treatment led to a dose-modifying effect of 1.2 in one fraction per day schedules but had no significant effect in three fractions per day schedules. The present results may provide guidelines for clinical application of irradiation schedules with more than one fraction per day.

Adenocarcinoma↗
PubMed1981

The role of energy in hyperthermia-induced mammalian cell inactivation: a study of the effects of glucose starvation and an uncoupler of oxidative phosphorylation.

When cultured Chinese hamster cells were exposed to 43 degrees C hyperthermia, effects due to glucose deprivation and to the presence of the uncoupler of oxidative phosphorylation, carbonylcyanide-3-chlorophenylhydrazone, during the 43 degrees C treatment proved to be strongly accelerated compared to the effects at normal temperature (37 degrees C). This strongly indicates that the availability of energy plays an important role in the response of these cells to hyperthermia. One of the reasons cells die after hyperthermia may be a lethal lack of energy. Cells heated before glucose deprivation were able to maintain viability for a longer period during deprivation than cells without the preheat treatment. As the cells might develop thermotolerance after the heat exposure, this suggests that cells in the thermotolerant state use energy in a more economical way.

Animals↗