Nicolaas (Klaas) A Franken | Academic Medical Centre/ Universiteit van Amsterdam (original) (raw)
Papers by Nicolaas (Klaas) A Franken
The British Journal of Radiology, 1997
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International Journal of Radiation Oncology*Biology*Physics, 1992
The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of... more The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of 20 Gy. The effects on myocardial norepinephrine concentrations and on alpha-adrenergic and beta-adrenergic receptor densities was examined up to 16 months post-treatment. Myocardial norepinephrine concentrations were reduced (to 50% of control values between 8 and 16 months) after irradiation. Receptor binding studies using radioactive ligands demonstrated that alpha-adrenergic receptor density was increased to maximally 210% of control values and that beta-adrenergic receptor density was increased to maximally 150% of control values, both measured at 8 months posttreatment. The affinities of both receptor types were not changed after irradiation. An inverse correlation was found between the myocardial norepinephrine concentration and the alpha-adrenergic receptor density. Myocardial norepinephrine concentration was not correlated to the beta-adrenergic receptor density. The changes in myocardial norepinephrine concentration and receptor density observed after irradiation suggest that even 16 months after irradiation overt cardiac failure was not occurring as the radiation-induced alterations differ considerably from those reported for failing hearts.
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Radiotherapy and Oncology, 1996
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Journal of Cancer Research and Clinical Oncology, 1998
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European heart journal, 1995
The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alko... more The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH-->GSSG), the glutathione reductase catalysed reaction (GSSG-->2GSH), or both. Neonatal rat heart cell cultures were subjected to a standardized protocol of oxidative stress using 80 mumol.l-1 cumene hydroperoxide (CHPO) for 0-90 min. The consequences of this protocol were described in terms of cellular concentrations of GSH, GSSG, NADPH and ATP, formation of malondialdehyde (MDA), release of GSSG and of ATP catabolites, depression of contraction frequency, cellular calcium overload, and enzyme release. Trolox-C, an analogue of vitamin E, accelerated the glutathione peroxidase reaction leading to lowering of GSH concentration and the GSH/GSSG ratio, less MDA formation, diminished negative chro...
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International Journal of Radiation Oncology*Biology*Physics, 1992
The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of... more The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of 20 Gy. The effects on myocardial norepinephrine concentrations and on alpha-adrenergic and beta-adrenergic receptor densities was examined up to 16 months post-treatment. Myocardial norepinephrine concentrations were reduced (to 50% of control values between 8 and 16 months) after irradiation. Receptor binding studies using radioactive ligands demonstrated that alpha-adrenergic receptor density was increased to maximally 210% of control values and that beta-adrenergic receptor density was increased to maximally 150% of control values, both measured at 8 months posttreatment. The affinities of both receptor types were not changed after irradiation. An inverse correlation was found between the myocardial norepinephrine concentration and the alpha-adrenergic receptor density. Myocardial norepinephrine concentration was not correlated to the beta-adrenergic receptor density. The changes in myocardial norepinephrine concentration and receptor density observed after irradiation suggest that even 16 months after irradiation overt cardiac failure was not occurring as the radiation-induced alterations differ considerably from those reported for failing hearts.
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Radiation Research, 1993
To investigate the effect of in vivo heart irradiation on myocardial energy metabolism, we measur... more To investigate the effect of in vivo heart irradiation on myocardial energy metabolism, we measured myocardial adenosine nucleotide concentrations and mitochondrial oxygen consumption in left ventricular tissue of rats 0-16 months after local heart irradiation (20 Gy). At 24 h and 2 months no difference in myocardial adenosine nucleotide concentration was apparent between irradiated and control hearts. The total myocardial adenosine nucleotide concentrations in irradiated hearts compared to those of nonirradiated controls tended to be lower from 4 months onward. The rate of oxidative energy production (state 3 respiration) in irradiated hearts was significantly reduced compared with that of age-matched controls from 2 months onward. Moreover, as a result of aging, a time-dependent decrease in the rate of oxidative energy production was observed in both irradiated and control hearts (P < 0.001). The respiratory control index (RCI = oxygen consumption in state 3/oxygen consumption in state 4) in irradiated hearts was not different from the RCI measured in age-matched control animals. During the period of study the RCI diminished significantly with age in both groups (P < 0.005). The number of oxygen atoms used per molecule of ADP phosphorylated (P/O ratio) was not influenced by the irradiation. The P/O ratio for the NAD(+)-linked substrates remained unchanged at a value of about 3 during the period studied. At 6 months after irradiation activities of myocardial enzymes such as lactate dehydrogenase, creatine kinase, citrate synthase, and cytochrome c oxidase were reduced. The reduction in myocardial energy production and the changes in energy supplies provide a mechanism to explain impaired contractility after local heart irradiation.
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In S and G2 phase mammalian cells DNA double strand breaks (DSBs) can potentially be repaired by ... more In S and G2 phase mammalian cells DNA double strand breaks (DSBs) can potentially be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). Results of several studies suggest that these two mechanistically distinct repair pathways can compete for DNA ends. Because HR and NHEJ differ with respect to error susceptibility, generation of chromosome rearrangements, which are potentially carcinogenic products of DSB repair, may depend on the pathway choice. To investigate this hypothesis, the influence of HR and NHEJ inhibition on the frequencies of chromosome aberrations in G2 phase cells was investigated. SW-1573 and RKO cells were treated with mild (41 • C) hyperthermia in order to disable HR and/or NU7441/cisplatin to inactivate NHEJ and frequencies of chromosomal fragments (resulting from unrepaired DSBs) and translocations (products of erroneous DSB rejoining) were studied using premature chromosome condensation (PCC) combined with fluorescence in situ hybridization (FISH). It is shown here that temporary inhibition of HR by hyperthermia results in increased frequency of ionizing-radiation (IR)-induced chromosomal translocations and that this effect is abrogated by NU7441-or cisplatin-mediated inhibition of NHEJ. The results suggest that in the absence of HR, DSB repair is shifted to the error-prone NHEJ pathway resulting in increased frequencies of chromosomal rearrangements. These results might be of consequence for clinical cancer treatment approaches that aim at inhibition of one or more DSB repair pathways.
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Radiation Research, 2016
Gamma-H2AX foci detection is the standard method to quantify DNA double-strand break (DSB) induct... more Gamma-H2AX foci detection is the standard method to quantify DNA double-strand break (DSB) induction and repair. In this study, we investigated the induction and decay of γ-H2AX foci of different tumor cell lines and fibroblasts with known mutations in DNA damage repair genes, including ATM, LigIV, DNA-PKcs, Rad51 and Rad54. A radiation dose of 2.4 Gy was used for either an acute single high-dose-rate (sHDR) exposure or a pulsed dose-rate (pDR) exposure over 24 h. The number of γ-H2AX foci was determined at 30 min and 24 h after sHDR irradiation and directly after pDR irradiation. In a similar manner, γ-H2AX foci were also examined in lymphocytes of patients with differences in normal tissue toxicity after a total radiation dose of 1 Gy. In an initial count of the number of foci 30 min after sHDR irradiation, repair-proficient cell types could not be distinguished from repair-deficient cell types. However at 24 h postirradiation, while we observed a large decrease in foci numbers in NHEJ-proficient cells, the amount of γ-H2AX foci in cell types with mutated NHEJ repair remained at high levels. Except for IRS-1SF cells, HR-deficient cell types eventually did show a moderate decrease in foci number over time, albeit to a lesser extent than their corresponding parentals or repair-proficient control cells. In addition, analysis of γ-H2AX foci after sHDR exposure of patients with different sensitivity status clearly showed individual differences in radiation response. Radiosensitive patients could be distinguished from the more radioresistant patients with γ-H2AX foci decay ratios (initial number of foci divided by residual number of foci). Significantly higher decay ratios were observed in patients without toxicities, indicating more proficient repair compared to patients with radiation-induced side effects. After pDR irradiation, no consistent correlation could be found between foci number and radiosensitivity. In conclusion, γ-H2AX formation is a rapid and sensitive cellular response to DNA DSBs. Decay ratios after sHDR exposure elucidated large differences in γ-H2AX foci kinetics between the repair-proficient or -deficient cell types and patients. This assay may be useful for measuring cellular radiosensitivity and could serve as a clinically useful test for predicting radiosensitivity ex vivo before treatment.
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International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, Jan 15, 2015
Planning of combined radiotherapy and hyperthermia treatments should be performed taking the syne... more Planning of combined radiotherapy and hyperthermia treatments should be performed taking the synergistic action between the two modalities into account. This work evaluates the available experimental data on cytotoxicity of combined radiotherapy and hyperthermia treatment and the requirements for integration of hyperthermia and radiotherapy treatment planning into a single planning platform. The underlying synergistic mechanisms of hyperthermia include inhibiting DNA repair, selective killing of radioresistant hypoxic tumour tissue and increased radiosensitivity by enhanced tissue perfusion. Each of these mechanisms displays different dose-effect relations, different optimal time intervals and different optimal sequences between radiotherapy and hyperthermia. Radiosensitisation can be modelled using the linear-quadratic (LQ) model to account for DNA repair inhibition by hyperthermia. In a recent study, an LQ model-based thermoradiotherapy planning (TRTP) system was used to demonstra...
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International Journal of Molecular Medicine, 2011
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Radioprotection, 2008
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Cancer research, Jan 16, 2015
Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in wo... more Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42°C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion ...
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European Heart Journal
The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alko... more The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH-->GSSG), the glutathione reductase catalysed reaction (GSSG-->2GSH), or both. Neonatal rat heart cell cultures were subjected to a standardized protocol of oxidative stress using 80 mumol.l-1 cumene hydroperoxide (CHPO) for 0-90 min. The consequences of this protocol were described in terms of cellular concentrations of GSH, GSSG, NADPH and ATP, formation of malondialdehyde (MDA), release of GSSG and of ATP catabolites, depression of contraction frequency, cellular calcium overload, and enzyme release. Trolox-C, an analogue of vitamin E, accelerated the glutathione peroxidase reaction leading to lowering of GSH concentration and the GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, delayed calcium overload, and less enzyme release. Glucose was used to accelerate the glutathione reductase reaction by supplying NADPH, leading to higher GSH concentration and a higher GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, unchanged development of calcium overload, and less enzyme release. As a full turn of the glutathione redox cycle involves both the peroxidase and the reductase reactions, the combination of Trolox-C and glucose was superior to either of the two alone: 90 min following addition of CHPO together with Trolox-C and glucose, the GSH concentration and the GSH/GSSG ratio were almost normal, MDA formation was extremely low, calcium overload was markedly delayed, and enzyme release hardly occurred at all. Cells remained beating in the observation period of 30 min. We conclude that the capacity of the glutathione redox cycle to withstand oxidative stress can be increased by stimulation of either the peroxidase reaction or the reductase reaction, and that optimal redox cycling is achieved by stimulation of both reactions.
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Tijdschrift voor gerontologie en geriatrie
To investigate radiosensitization by halogenated pyrimidines in human cells, SW-1573 lung tumor c... more To investigate radiosensitization by halogenated pyrimidines in human cells, SW-1573 lung tumor cells were grown in absence or presence of 4 mu M of iododeoxyuridine (IdUrd). Cell survival after irradiation with gamma-rays from a Cs-137 source with single doses up to 8 Gy, was determined by clonogenic assay, Radiosensitization by IdUrd was observed in both exponentially growing and plateau phase cells. Linear-quadratic analyses of the radiation survival curves demonstrated that radiosensitization was mainly expressed by an increase of the value of alpha (determining the initial slope of the survival curve) which can be interpreted as an enhancement of fixation of potentially lethal damage (PLD). The value of beta (determining the curvature of the survival curve), which might be attributed to enhanced interaction or to fixation of sublethal damage (SLD), was not influenced. In view of clinical applications of IdUrd it is of interest that radiosensitization has its main effect in the low dose region of the cell survival curve, described by the linear term alpha D.
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Ophthalmologica
[123I]-5-iodo-2-thiouracil (123I-ITU) was evaluated as a radiopharmaceutical for tumor detection ... more [123I]-5-iodo-2-thiouracil (123I-ITU) was evaluated as a radiopharmaceutical for tumor detection in 10 patients with proven choroidal melanoma. Uptake of 123I-ITU was measured with a specially designed single eye probe collimator, 24 h after administration of 123I-ITU. Increased uptake in the tumor-bearing eye as compared to the fellow nontumor bearing eye was found in 7 out of 10 cases when the probe was located 3.5 cm in front of the eye (p less than 0.01). By using a double pinhole collimator tests were positive in 3 out of 10 123I-ITU studies only. Tests with 123I-ITU were compared with 67Ga tests in the same patients. The 67Ga tests with the single eye probe collimator were positive in 6 out 10 cases when the probe was located 6 cm in front of the eye. With the double pinhole collimator tests were positive in 7 out of 10 67Ga studies. It is concluded that 123I-labeled thiouracil is at least as useful as a radiopharmaceutical for ocular melanoma diagnosis as 67Ga-citrate, provided measurements are performed with a single eye probe.
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The British Journal of Radiology, 1997
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International Journal of Radiation Oncology*Biology*Physics, 1992
The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of... more The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of 20 Gy. The effects on myocardial norepinephrine concentrations and on alpha-adrenergic and beta-adrenergic receptor densities was examined up to 16 months post-treatment. Myocardial norepinephrine concentrations were reduced (to 50% of control values between 8 and 16 months) after irradiation. Receptor binding studies using radioactive ligands demonstrated that alpha-adrenergic receptor density was increased to maximally 210% of control values and that beta-adrenergic receptor density was increased to maximally 150% of control values, both measured at 8 months posttreatment. The affinities of both receptor types were not changed after irradiation. An inverse correlation was found between the myocardial norepinephrine concentration and the alpha-adrenergic receptor density. Myocardial norepinephrine concentration was not correlated to the beta-adrenergic receptor density. The changes in myocardial norepinephrine concentration and receptor density observed after irradiation suggest that even 16 months after irradiation overt cardiac failure was not occurring as the radiation-induced alterations differ considerably from those reported for failing hearts.
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Radiotherapy and Oncology, 1996
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Journal of Cancer Research and Clinical Oncology, 1998
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European heart journal, 1995
The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alko... more The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH-->GSSG), the glutathione reductase catalysed reaction (GSSG-->2GSH), or both. Neonatal rat heart cell cultures were subjected to a standardized protocol of oxidative stress using 80 mumol.l-1 cumene hydroperoxide (CHPO) for 0-90 min. The consequences of this protocol were described in terms of cellular concentrations of GSH, GSSG, NADPH and ATP, formation of malondialdehyde (MDA), release of GSSG and of ATP catabolites, depression of contraction frequency, cellular calcium overload, and enzyme release. Trolox-C, an analogue of vitamin E, accelerated the glutathione peroxidase reaction leading to lowering of GSH concentration and the GSH/GSSG ratio, less MDA formation, diminished negative chro...
Bookmarks Related papers MentionsView impact
International Journal of Radiation Oncology*Biology*Physics, 1992
The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of... more The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of 20 Gy. The effects on myocardial norepinephrine concentrations and on alpha-adrenergic and beta-adrenergic receptor densities was examined up to 16 months post-treatment. Myocardial norepinephrine concentrations were reduced (to 50% of control values between 8 and 16 months) after irradiation. Receptor binding studies using radioactive ligands demonstrated that alpha-adrenergic receptor density was increased to maximally 210% of control values and that beta-adrenergic receptor density was increased to maximally 150% of control values, both measured at 8 months posttreatment. The affinities of both receptor types were not changed after irradiation. An inverse correlation was found between the myocardial norepinephrine concentration and the alpha-adrenergic receptor density. Myocardial norepinephrine concentration was not correlated to the beta-adrenergic receptor density. The changes in myocardial norepinephrine concentration and receptor density observed after irradiation suggest that even 16 months after irradiation overt cardiac failure was not occurring as the radiation-induced alterations differ considerably from those reported for failing hearts.
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Radiation Research, 1993
To investigate the effect of in vivo heart irradiation on myocardial energy metabolism, we measur... more To investigate the effect of in vivo heart irradiation on myocardial energy metabolism, we measured myocardial adenosine nucleotide concentrations and mitochondrial oxygen consumption in left ventricular tissue of rats 0-16 months after local heart irradiation (20 Gy). At 24 h and 2 months no difference in myocardial adenosine nucleotide concentration was apparent between irradiated and control hearts. The total myocardial adenosine nucleotide concentrations in irradiated hearts compared to those of nonirradiated controls tended to be lower from 4 months onward. The rate of oxidative energy production (state 3 respiration) in irradiated hearts was significantly reduced compared with that of age-matched controls from 2 months onward. Moreover, as a result of aging, a time-dependent decrease in the rate of oxidative energy production was observed in both irradiated and control hearts (P < 0.001). The respiratory control index (RCI = oxygen consumption in state 3/oxygen consumption in state 4) in irradiated hearts was not different from the RCI measured in age-matched control animals. During the period of study the RCI diminished significantly with age in both groups (P < 0.005). The number of oxygen atoms used per molecule of ADP phosphorylated (P/O ratio) was not influenced by the irradiation. The P/O ratio for the NAD(+)-linked substrates remained unchanged at a value of about 3 during the period studied. At 6 months after irradiation activities of myocardial enzymes such as lactate dehydrogenase, creatine kinase, citrate synthase, and cytochrome c oxidase were reduced. The reduction in myocardial energy production and the changes in energy supplies provide a mechanism to explain impaired contractility after local heart irradiation.
Bookmarks Related papers MentionsView impact
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In S and G2 phase mammalian cells DNA double strand breaks (DSBs) can potentially be repaired by ... more In S and G2 phase mammalian cells DNA double strand breaks (DSBs) can potentially be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). Results of several studies suggest that these two mechanistically distinct repair pathways can compete for DNA ends. Because HR and NHEJ differ with respect to error susceptibility, generation of chromosome rearrangements, which are potentially carcinogenic products of DSB repair, may depend on the pathway choice. To investigate this hypothesis, the influence of HR and NHEJ inhibition on the frequencies of chromosome aberrations in G2 phase cells was investigated. SW-1573 and RKO cells were treated with mild (41 • C) hyperthermia in order to disable HR and/or NU7441/cisplatin to inactivate NHEJ and frequencies of chromosomal fragments (resulting from unrepaired DSBs) and translocations (products of erroneous DSB rejoining) were studied using premature chromosome condensation (PCC) combined with fluorescence in situ hybridization (FISH). It is shown here that temporary inhibition of HR by hyperthermia results in increased frequency of ionizing-radiation (IR)-induced chromosomal translocations and that this effect is abrogated by NU7441-or cisplatin-mediated inhibition of NHEJ. The results suggest that in the absence of HR, DSB repair is shifted to the error-prone NHEJ pathway resulting in increased frequencies of chromosomal rearrangements. These results might be of consequence for clinical cancer treatment approaches that aim at inhibition of one or more DSB repair pathways.
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Radiation Research, 2016
Gamma-H2AX foci detection is the standard method to quantify DNA double-strand break (DSB) induct... more Gamma-H2AX foci detection is the standard method to quantify DNA double-strand break (DSB) induction and repair. In this study, we investigated the induction and decay of γ-H2AX foci of different tumor cell lines and fibroblasts with known mutations in DNA damage repair genes, including ATM, LigIV, DNA-PKcs, Rad51 and Rad54. A radiation dose of 2.4 Gy was used for either an acute single high-dose-rate (sHDR) exposure or a pulsed dose-rate (pDR) exposure over 24 h. The number of γ-H2AX foci was determined at 30 min and 24 h after sHDR irradiation and directly after pDR irradiation. In a similar manner, γ-H2AX foci were also examined in lymphocytes of patients with differences in normal tissue toxicity after a total radiation dose of 1 Gy. In an initial count of the number of foci 30 min after sHDR irradiation, repair-proficient cell types could not be distinguished from repair-deficient cell types. However at 24 h postirradiation, while we observed a large decrease in foci numbers in NHEJ-proficient cells, the amount of γ-H2AX foci in cell types with mutated NHEJ repair remained at high levels. Except for IRS-1SF cells, HR-deficient cell types eventually did show a moderate decrease in foci number over time, albeit to a lesser extent than their corresponding parentals or repair-proficient control cells. In addition, analysis of γ-H2AX foci after sHDR exposure of patients with different sensitivity status clearly showed individual differences in radiation response. Radiosensitive patients could be distinguished from the more radioresistant patients with γ-H2AX foci decay ratios (initial number of foci divided by residual number of foci). Significantly higher decay ratios were observed in patients without toxicities, indicating more proficient repair compared to patients with radiation-induced side effects. After pDR irradiation, no consistent correlation could be found between foci number and radiosensitivity. In conclusion, γ-H2AX formation is a rapid and sensitive cellular response to DNA DSBs. Decay ratios after sHDR exposure elucidated large differences in γ-H2AX foci kinetics between the repair-proficient or -deficient cell types and patients. This assay may be useful for measuring cellular radiosensitivity and could serve as a clinically useful test for predicting radiosensitivity ex vivo before treatment.
Bookmarks Related papers MentionsView impact
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, Jan 15, 2015
Planning of combined radiotherapy and hyperthermia treatments should be performed taking the syne... more Planning of combined radiotherapy and hyperthermia treatments should be performed taking the synergistic action between the two modalities into account. This work evaluates the available experimental data on cytotoxicity of combined radiotherapy and hyperthermia treatment and the requirements for integration of hyperthermia and radiotherapy treatment planning into a single planning platform. The underlying synergistic mechanisms of hyperthermia include inhibiting DNA repair, selective killing of radioresistant hypoxic tumour tissue and increased radiosensitivity by enhanced tissue perfusion. Each of these mechanisms displays different dose-effect relations, different optimal time intervals and different optimal sequences between radiotherapy and hyperthermia. Radiosensitisation can be modelled using the linear-quadratic (LQ) model to account for DNA repair inhibition by hyperthermia. In a recent study, an LQ model-based thermoradiotherapy planning (TRTP) system was used to demonstra...
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International Journal of Molecular Medicine, 2011
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Radioprotection, 2008
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Cancer research, Jan 16, 2015
Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in wo... more Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42°C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion ...
Bookmarks Related papers MentionsView impact
European Heart Journal
The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alko... more The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH-->GSSG), the glutathione reductase catalysed reaction (GSSG-->2GSH), or both. Neonatal rat heart cell cultures were subjected to a standardized protocol of oxidative stress using 80 mumol.l-1 cumene hydroperoxide (CHPO) for 0-90 min. The consequences of this protocol were described in terms of cellular concentrations of GSH, GSSG, NADPH and ATP, formation of malondialdehyde (MDA), release of GSSG and of ATP catabolites, depression of contraction frequency, cellular calcium overload, and enzyme release. Trolox-C, an analogue of vitamin E, accelerated the glutathione peroxidase reaction leading to lowering of GSH concentration and the GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, delayed calcium overload, and less enzyme release. Glucose was used to accelerate the glutathione reductase reaction by supplying NADPH, leading to higher GSH concentration and a higher GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, unchanged development of calcium overload, and less enzyme release. As a full turn of the glutathione redox cycle involves both the peroxidase and the reductase reactions, the combination of Trolox-C and glucose was superior to either of the two alone: 90 min following addition of CHPO together with Trolox-C and glucose, the GSH concentration and the GSH/GSSG ratio were almost normal, MDA formation was extremely low, calcium overload was markedly delayed, and enzyme release hardly occurred at all. Cells remained beating in the observation period of 30 min. We conclude that the capacity of the glutathione redox cycle to withstand oxidative stress can be increased by stimulation of either the peroxidase reaction or the reductase reaction, and that optimal redox cycling is achieved by stimulation of both reactions.
Bookmarks Related papers MentionsView impact
Tijdschrift voor gerontologie en geriatrie
To investigate radiosensitization by halogenated pyrimidines in human cells, SW-1573 lung tumor c... more To investigate radiosensitization by halogenated pyrimidines in human cells, SW-1573 lung tumor cells were grown in absence or presence of 4 mu M of iododeoxyuridine (IdUrd). Cell survival after irradiation with gamma-rays from a Cs-137 source with single doses up to 8 Gy, was determined by clonogenic assay, Radiosensitization by IdUrd was observed in both exponentially growing and plateau phase cells. Linear-quadratic analyses of the radiation survival curves demonstrated that radiosensitization was mainly expressed by an increase of the value of alpha (determining the initial slope of the survival curve) which can be interpreted as an enhancement of fixation of potentially lethal damage (PLD). The value of beta (determining the curvature of the survival curve), which might be attributed to enhanced interaction or to fixation of sublethal damage (SLD), was not influenced. In view of clinical applications of IdUrd it is of interest that radiosensitization has its main effect in the low dose region of the cell survival curve, described by the linear term alpha D.
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Ophthalmologica
[123I]-5-iodo-2-thiouracil (123I-ITU) was evaluated as a radiopharmaceutical for tumor detection ... more [123I]-5-iodo-2-thiouracil (123I-ITU) was evaluated as a radiopharmaceutical for tumor detection in 10 patients with proven choroidal melanoma. Uptake of 123I-ITU was measured with a specially designed single eye probe collimator, 24 h after administration of 123I-ITU. Increased uptake in the tumor-bearing eye as compared to the fellow nontumor bearing eye was found in 7 out of 10 cases when the probe was located 3.5 cm in front of the eye (p less than 0.01). By using a double pinhole collimator tests were positive in 3 out of 10 123I-ITU studies only. Tests with 123I-ITU were compared with 67Ga tests in the same patients. The 67Ga tests with the single eye probe collimator were positive in 6 out 10 cases when the probe was located 6 cm in front of the eye. With the double pinhole collimator tests were positive in 7 out of 10 67Ga studies. It is concluded that 123I-labeled thiouracil is at least as useful as a radiopharmaceutical for ocular melanoma diagnosis as 67Ga-citrate, provided measurements are performed with a single eye probe.
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