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J Haveman

Publications and source records attributed to J Haveman.

At least 19 recordsLinked to original sources
PubMed2000

The effect of p53-function on the sensitivity to paclitaxel with or without hyperthermia in human colorectal carcinoma cells.

The importance of p53-function for the sensitivity to paclitaxel with and without hyperthermia (HT) was studied in an isogenic cell line system. The inactivation of p53 decreased sensitivity to paclitaxel (1.1-2.5-fold), which correlated with a lower induction of apoptosis. The magnitude of the G2/M arrest after treatment with paclitaxel was similar in all cell lines. The cytotoxicity of paclitaxel was not enhanced by HT in either wild-type p53 or p53-inactivated cells. In conclusion, cellular sensitivity to paclitaxel depends on p53-function by its ability to induce apoptosis. Irrespective of the p53-function HT was not able to enhance the sensitivity to paclitaxel.

Antineoplastic Agents, Phytogenic↗
PubMed1999

[Hyperthermia in combination with radiotherapy].

The clinical application of hyperthermia in the treatment of oncological patients is based on a strong biological rationale: hyperthermia is an effective cell-killing agent, the effects of which can be induced selectively in tumour tissue. The mechanism of action of hyperthermia is complementary to that of radiotherapy (and chemotherapy). Furthermore, hyperthermia enhances the effects of radiotherapy (and of chemotherapy). In the approximately 20 years that hyperthermia was clinically investigated, much progress was made in the techniques of application. The clinical results achieved so far show that the therapeutic gain by adding hyperthermia can indeed be substantial.

Combined Modality Therapy↗
PubMed1999

Inactivation of p53 and of pRb protects human colorectal carcinoma cells against hyperthermia-induced cytotoxicity and apoptosis.

Cell-cycle checkpoints are thought to govern the cellular response to external stimuli. The involvement of the p53 tumour-suppressor protein and the retinoblastoma protein (pRb) in the cell-cycle checkpoint in G1 phase is well established. However, little is known about the importance of these G1 checkpoint regulators in hyperthermia-induced cytotoxicity. Such information is relevant because of the clinical application of hyperthermia in combination with chemotherapy or with radiotherapy. The effects of p53 or pRb inactivation were studied in a well-established isogenic system using the human colorectal carcinoma cell line (RKO). The cells were treated with clinically relevant heat doses (60 min at 40-43 degrees C). Cell survival, cell-cycle redistribution and induction of apoptosis were investigated. Survival of the p53-inactivated transfectants was higher than that of the wild-type p53 cells. The pRb-inactivated transfectants showed an intermediate sensitivity to hyperthermia. All transfectants showed G2 arrest after hyperthermia and the appearance of a sub-G1 population. The induction of apoptosis was inhibited in p53-inactivated and pRb-inactivated transfectants. These results suggest that p53 and/or pRb status may be an important determinant of the clinical response to hyperthermia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells.

The cytotoxicity of cisplatin and cisplatin-DNA adduct formation in vitro and in vivo is clearly enhanced by hyperthermia. We investigated whether cytotoxicity and platinum-DNA adduct formation of two promising new third-generation platinum derivatives, lobaplatin [1,2-diamminomethylcyclobutane platinum(II) lactate] and oxaliplatin [oxalato-1,2-diaminocyclohexane platinum(II)], are also enhanced by hyperthermia. Cisplatin was used for comparison. SW 1573 cells were incubated with cisplatin, lobaplatin or oxaliplatin at different concentrations for 1 h at 37 degrees, 41 degrees and 43 degrees C. The reproductive capacity of cells was determined by cloning experiments. Immunocytochemical detection of platinum-DNA adducts was performed with the rabbit antiserum NKI-A59. At 37 degrees C, cisplatin was the most cytotoxic, followed by oxaliplatin and lobaplatin. Hyperthermia clearly enhanced the cytotoxicity of cisplatin, lobaplatin and oxaliplatin. There was no further increase in cytotoxicity at 43 degrees C compared to 41 degrees C for cisplatin and oxaliplatin. A further increase in cytotoxicity at 43 degrees C was observed for lobaplatin. At 43 degrees C thermal enhancement was higher for lobaplatin than for oxaliplatin, with the reverse pattern at 41 degrees C. For both drugs, thermal enhancement of cytotoxicity was lower than observed for cisplatin. Immunocytochemical detection of platinum-DNA adducts was feasible for all the drugs. Adduct formation was enhanced at 43 degrees C for cisplatin, lobaplatin and oxaliplatin with a relative increase of 410%, 170% and 180%. These results seem to confirm that an increase in platinum-DNA adduct formation is involved in the in vitro thermal enhancement of cytotoxicity. The observed thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin in vitro warrants further in vivo investigations.

Antineoplastic Agents↗
PubMed1996

Collagen content in rat liver after experimentally induced cholestasis followed by choledochojejunostomy and X-irradiation.

The right part of the median lobe of the liver of female Wistar rats was irradiated, 12.5 or 25 Gy, at a field size of 15 x 20 mm. The central part of the irradiated liver lobe was fixed and used for the estimation of the collagen protein ratio by means of the Sirius Red-Fast Green extraction method, immediately, 8, 16 or 32 weeks after irradiation. No significant increase in collagen content could be demonstrated in this time range, both after irradiation at 12.5 Gy and at 25 Gy. Partial hepatectomy according to Higgins led to rapid regrowth of the remaining liver lobes. The right lobe grew out rapidly to replace the median lobe. Two days after partial hepatectomy the right lobe was irradiated at the same field size. Measurement of the collagen protein ratio in this experiment did not show a significant increase 8, 16 or 32 weeks after irradiation. However, the 25 Gy group did not survive long enough to obtain data at 16 or 32 weeks. The animals in this latter experiment suffered from ascites before dying. Experimentally induced cholestasis was obtained by ligation and partial resection of the common bile duct. After two weeks of cholestasis the bile flow was restored by Roux-en-Y choledochojejunostomy. The effect of irradiation 2 days after repair surgery was studied. Without irradiation the collagen protein ratio is increased. Irradiation of the right part of the median lobe led to a relatively enhanced collagen content in this lobe. Our results indicate that radiation itself does not lead to a significantly enhanced degree of fibrosis in the liver. However when an increase in collagen content was induced by cholestasis, the partial "dilution" of enhanced fibrosis as a result of proliferation of liver parenchyma cells following repair surgery was inhibited by irradiation.

Animals↗
PubMed1995

Effect of hyperthermia on the cytotoxicity of 2',2'-difluorodeoxycytidine (gemcitabine) in cultured SW1573 cells.

Difluorodeoxycytidine (dFdCyd, gemcitabine) was tested for cytotoxicity in cultured human lung-cancer cells SW1573 in combination with 1 hr hyperthermia at 43 degrees C. The results show that the timing is extremely important. Simultaneous application led to decreased cytotoxicity, whereas an interval of 20 or 24 hr between exposure to dFdCyd and hyperthermia led to enhanced cell killing. The decrease in cytotoxicity after simultaneous hyperthermia and dFdCyd probably results from inhibition of activation of dFdCyd to the triphosphate metabolite. The enhanced cytotoxicity in sequential application of dFdCyd and hyperthermia is not caused by accumulation of cells in a sensitive cell-cycle phase. Our results show that the G1 phase becomes relatively abundant 20 hr after exposure to 0.1 microM dFdCyd, approximately 48% versus 31% in control cultures. Presumably, inhibition by hyperthermia of repair of DNA damage plays a role. Our results confirm earlier data with regard to reutilization of activated dFdCyd at high cell density. dFdCyd was clearly more toxic to SW1573 cells at 4 x 10(5) cells per dish than at 400 cells per dish. This reutilization of activated drug is evidently not a restricted property of a particular cell line and may add to the value of the drug in cancer treatment.

Carcinoma, Squamous Cell↗
PubMed1995

Neurological observations after local irradiation and hyperthermia of rat lumbosacral spinal cord.

PURPOSE: Investigation of the effects of hyperthermia on the radiation response of rat lumbosacral spinal cord with respect to: (a) incidence of paralysis, (b) latency, (c) histopathology, and (d) tumor induction. METHODS AND MATERIALS: Rat lumbosacral spinal cord with the cauda equina was single-dose irradiated with 15 to 32 Gy of x-rays. Hyperthermia for 30 min at a spinal cord temperature of 41.1, 42.3, and 42.6 +/- 0.4 degrees C was applied 5 to 10 min after irradiation by means of a 434 MHz microwave applicator. Animals were observed for 21 months while recording myelopathy and development of tumors. RESULTS: The latent period for hind leg paralysis decreased with increasing radiation dose from 359 +/- 31 days (n = 9) after 20 Gy to 200 +/- 4 days (n = 5) after 32 Gy. Hyperthermia enhanced the radiation response of the lumbosacral spinal cord as evidenced by shortening of the latent period for paralysis and a decrease in the biological effective dose. After 20 Gy followed by 30 min 41.1 degrees C, latency was diminished to 214 +/- 16 days (n = 7, p < 0.001 vs. 20 Gy alone). The ED50 was 21.1 Gy, which was diminished to values between 16 and 17 Gy if radiation was followed by hyperthermia, giving a thermal enhancement ratio between 1.24 and 1.32. Histopathological examination of the spinal cord after combined treatment of x-rays and hyperthermia showed necrosis of nerve roots. Irradiation with 16, 20, 24, and 28 Gy (n = 77) alone led to tumor induction in 17 +/- 8% of the animals (pooled data). If followed by hyperthermia (n = 96), it was increased to 33 +/- 12% (p < 0.01). Most tumors induced by radiation and hyperthermia were sarcomas. CONCLUSION: First, the radiation response of rat lumbosacral spinal cord was enhanced by heat. Second, latency for paralysis was shortened in the lower dose range. Third, no difference in pathology between x-rays alone or in combination with hyperthermia. Fourth, hyperthermia did increase radiation carcinogenesis.

Animals↗
PubMed1993

Latent X-ray damage in the rat sciatic nerve results in delay in functional recovery after a heat treatment.

The influence of X-irradiation on the sensitivity of the rat sciatic nerve to local hyperthermia was investigated. A 10 or 20 mm long segment of the nerve was irradiated intraoperatively using 50 kV X-rays. Hyperthermia (30 min at 45 degrees C), was applied to the irradiated part (over a length of 5 mm) of the nerve using a brass thermode. Functional damage to the nerve was assessed using the toe-spreading test, which mainly assesses the motor function of the sciatic nerve. Radiation alone (doses up to 70 Gy) did not lead to detectable damage for at least 90 weeks. Hyperthermia alone (30 min at 45 degrees C) resulted in complete loss of motor function. This function loss was transient and complete recovery took place in about 4 weeks. Recovery time was scored as the number of days between hyperthermia and the day on which 50% of the motor function had returned. Irradiation (35 Gy) of a nerve segment, which included the heated part, resulted in a delayed recovery from the heat treatment compared to controls (heat only). The time interval and sequence between irradiation and hyperthermia hardly influenced the recovery delay. The size of the irradiated nerve segment did influence the recovery delay. Irradiation of a 20 mm nerve segment led to longer recovery delays than irradiation of a 10 mm segment (a delay of 5-10 days and 1-5 days respectively). A dose-response relation for the irradiation-induced delay in recovery was observed when a large segment (20 mm) of the nerve was irradiated immediately after heat with a dose ranging from 5 to 40 Gy. The delay in heat recovery was dose-dependent below 20 Gy, but after radiation doses above 20 Gy the recovery delay remained almost constant.

Animals↗
PubMed1993

Influence of cisplatin on the sensitivity of the rat sciatic nerve to local hyperthermia.

The influence of cisplatin on the sensitivity of the rat sciatic nerve to local hyperthermia was investigated. Rats received 1.7 mg/kg cisplatin i.p., twice a week for 6 weeks, up to a cumulative dose of 20.4 mg/kg. After termination of cisplatin treatment, a 5 mm segment of the nerve was locally heated at a temperature of 45 degrees C (5-30 min). Loss of motor function was assessed by means of the toe-spreading test, 24 h post heating. The calculated ED50 for control nerves was significantly (p < 0.01) larger than the ED50 for cisplatin treated rats; 16.3 +/- 1.1 min vs. 10.9 +/- 1.1 min. This indicates that nerves from cisplatin treated rats were more sensitive to heat than nerves from control rats (dose modifying factor = 1.5 +/- 0.2). Histopathological investigation of nerves after heat alone or after heat preceded by cisplatin confirmed these differences and showed that edema, vascular damage and axonal degenerative changes of axons and myelin sheaths occurred at lower heat doses when compared to control nerves. Recovery studies showed that cisplatin treatment before hyperthermia caused a delay in recovery from motor function loss of about 6 days. Cisplatin treatment after hyperthermia had no influence on recovery from motor function loss.

Animals↗
PubMed1992

Hyperthermic injury versus crush injury in the rat sciatic nerve: a comparative functional, histopathological and morphometrical study.

Functional and morphological changes of the rat sciatic nerve after local hyperthermia (30 min, 45 degrees C) and crush treatment were compared. After hyperthermic injury nerve function loss developed in a time period of about 7 h. Nerve crush led to an immediate loss of nerve function. Nerve function loss was assessed by a motor and a sensory function test. Recovery from function loss took place in both treatment groups and was complete in 4-5 weeks. Early (within 8 h post-treatment) histopathological changes in the nerve after heating included edema, possible blood stasis and changes in the blood vessel wall, like swelling of the media. During this period some axonal changes were observed. Immediate after crushing axons were severely damaged, while many blood vessels remained normal. Within one week after both treatments, degeneration of axons and myelin was observed at the site and distal from the site of the lesion (Wallerian degeneration). Three weeks after treatment a major part of the axons had regenerated and remyelinated. Vascular changes at the site of lesion could still be observed in the heat-treated nerves. Twelve weeks after both treatments, blood vessels appeared to be normal again. Morphometrical analysis of the treated nerves confirmed the histological observations. Three and 12 weeks after treatment average axon diameters were significant smaller and average myelin sheaths were significant thinner compared to untreated nerves. These parameters did not differ significantly when the two treatment groups were compared.

Animals↗
PubMed1992

Hyperthermia-induced damage to rat sciatic nerve assessed in vivo with functional methods and with electrophysiology.

A 5-mm segment of the rat sciatic nerve was treated in vivo with hyperthermia (43-45 degrees C) for different times using a brass thermode. The effect of this local heat treatment on the nerve was assessed with electrophysiology and using two functional assays. Hyperthermia led to a dose-dependent decrease of motor and sensory function. Electrophysiological examination showed a decrease in amplitude of motor and reflex responses rather than a decrease in conduction velocities. Calculated ED50 values were not significantly different for the two functional and for the electrophysiological methods. Functional recovery from nerve damage took place in all cases. Measured at the same level of damage, i.e., 50% function loss, it took 14 days to recover from complete sensory function loss and 20 days from complete motor function loss. Although both motor and sensory functions were restored, 30 days after hyperthermia no responses could be detected with electrophysiology, this as a result of the thin myelin sheaths that occur upon recovery.

Animals↗
PubMed1992

The influence of hyperthermia on the uptake of cisplatin in the rat cervical spinal cord.

The influence of local hyperthermia on the uptake of cisplatin in the rat cervical spinal cord was investigated. After single intraperitoneal or intravenous injection of cisplatin (5 mg/kg body weight), the spinal cord region cervical 5-thoracic 2 was heated for 60 min at mean (S.D.) 41.2 (0.4) degrees C or 40 min 42.4 (0.3) degrees C using a 434 MHz microwave heating device. One day after treatment with either hyperthermia alone, cisplatin alone or the combination, none of the animals expressed neurological symptoms. The spinal cord was dissected and platinum levels were measured by flameless atomic absorption spectroscopy. No difference was found in uptake of platinum in the spinal cord between control- and heat treated animals. In a second series of experiments, the spinal cord was heated for 30-60 min. during a 2 h infusion of cisplatin. One day after treatment at 42.3 degrees C for 60 min, neither motor nor sensory functions were affected and platinum levels did not differ significantly between control and treated animals. Also, platinum levels measured in the spinal cord immediately after cisplatin infusion were not influenced by heat treatment at 42.1 or 43.0 degrees C for 30 min. However, after a heat dose of 60 min 43 degrees C, cisplatin uptake was significantly increased (P less than 0.001) by a factor of 2.8 (1.3). The data demonstrate that mild hyperthermia has no effect on the uptake of cisplatin in the spinal cord, while an injurious heat dose leads to a significant increase in cisplatin uptake. The present findings indicate that, in case of treatment of tumours of the central nervous system with hyperthermia and cisplatin, a treatment which might be toxic for the tumour is well tolerated by the normal nervous tissue.

Animals↗
PubMed1992

Neurological complications after 434 MHz microwave hyperthermia of the rat lumbar region including the spinal cord.

Hyperthermia was applied in the region of the vertebral column from the second to the fifth lumbar vertebra using a ring-shaped 434 MHz microwave radiator. In all experiments temperatures were measured at a 'reference' thermocouple which was placed against the fourth lumbar vertebra. After 60 min of heat treatment at 'reference' temperatures of 43.0 degrees C, 44.0 degrees C and 45.0 degrees C (+/- 0.05 degrees C) the average maximal temperature inside the vertebral canal were 42.6 degrees C, 43.0 degrees C and 43.8 degrees C (+/- 0.3 degrees C), respectively. At all 'reference' temperatures the maximal core temperature of the animal did not exceed 40.5 +/- 0.3 degrees C after 60 min of heat treatment. Dorsal skin and muscle temperatures in the treatment area reached 'reference' temperature, and transient skin and muscle necrosis was observed after treatment for 1 h at 'reference' temperatures at 44 degrees C and 45 degrees C. Temperatures in the peritoneal cavity approximately 1 mm ventrally of the vertebral column rose to 41.8 degrees C after 60 min at reference 43.0 degrees C. Treatment at spinal cord temperature 42.6 degrees C for 60 min did not induce any significant neurological effects. Motoric dysfunction of the hind legs, such as difficulties with walking, was observed after 60 min treatment at spinal cord temperatures of 43.0 degrees C or 43.8 degrees C. In addition, 24 h after treatment at 43.8 degrees C for 60 min loss of tail tonus was observed, as well as loss of sensory function in the hind limbs. Recovery from the neurological disorders, except for the loss of tail tonus, occurred within 2 weeks after treatment. Histopathological examination revealed necrosis in the central areas of the spinal cord at 3 days and complete necrosis at 7 days after treatment at 43.8 degrees C for 60 min.

Animals↗
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↗