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W Landuyt

Publications and source records attributed to W Landuyt.

At least 37 records · Page 2Linked to original sources
PubMed2000

Vascular targeting of solid tumours: a major 'inverse' volume-response relationship following combretastatin A-4 phosphate treatment of rat rhabdomyosarcomas.

Tumour-specific vascularisation may be therapeutically approached in two different ways: by antiangiogenic treatments specifically directed to dividing and migrating endothelial cells, or by agents that target principally the inadequate and ill-structured tumour vasculature. Combretastatin A-4 phosphate (combreAp), a recently synthesised prodrug (OXiGENE, Lund, Sweden), is a vascular targeting agent of the latter kind. We evaluated the effect of a single intraperitoneal (i.p.) combreAp injection on the growth of rhabdomyosarcomas syngeneic in WAG/Rij rats. Different tumour volume groups, ranging between 0.1 and 27 cm(3), were selected to assess the relationship between the size at treatment time and the response to combreAp. A double combreAp treatment (2x25 mg/kg) was investigated within the same overall aim: the relationship between growth delay and tumour size. Our results show that the systemic administration of combreAp induces a clear-cut differential growth delay in the solid rat rhabdomyosarcomas: with very large tumours (>/= 14 cm(3)), a 17.6-fold stronger effect was measured than with very small tumours (<1 cm(3)). This is the 'inverse' of the volume-response seen with the conventional therapeutic approaches (radiotherapy, chemotherapy or surgery). These combreAp antitumour responses were observed without treatment limiting systemic toxicity in the rats. With clinical digital subtraction angiography, using microsurgical cannulation of a major tumour draining vessel, and with histopathology, we demonstrate that growth delay is related to an early (within 3-6 h) and extensive breakdown of tumour blood vessels. The experiments involving a second injection also indicate a volume-dependent effect of combreAp in reducing the regrowth rate of small or large rhabdomyosarcomas. This significant differential volume-response obtained with 'selective' vascular targeting, stronger in larger tumours than smaller ones, suggests the potential of broadening the therapeutic window.

Angiography, Digital Subtraction↗
PubMed2000

The potential therapeutic gain of radiation-associated gene therapy with the suicide gene cytosine deaminase.

PURPOSE: To estimate the concentration of 5-fluorocytosine (5-FC), necessary for conversion to 5-fluorouracil (5-FU) in tumours transduced with the gene cytosine deaminase (CD), to achieve clinically significant radiosensitization to radiotherapy. MATERIALS AND METHODS: Starting with a tumour control probability (TCP) of 37% from radiotherapy of 66 Gy in 2 Gy fractions, estimates were made of increase in TCP expected from sensitizer enhancement ratios (SER) of 1.1, 1.2, etc. SER values for 5-FU were obtained from a literature review. Clinical toxicity of 5-FC is also reviewed. RESULTS: 5-FU has been reported to be an effective radiosensitizer if maintained for several days after each irradiation at concentrations of 0.6-0.9 microg/ml in surrounding medium. 5-FC is well tolerated by patients at concentrations of 25-100 microg/ml (average 60 microg/ml) for 6 weeks in standard antifungal treatment. Sufficient 5-FU should be available if conversion efficiency from 5-FC is 1-3%. SER values of 1.1 to 1.2 should be achievable with daily 2 Gy fractions. In vitro and xenograft experiments are reviewed and they do not contradict the conclusions. CONCLUSIONS: Increases in tumour control of 20 to 40% can be expected, which should be detectable in a 2-arm randomized trial of 260 (for 20%) or 60 (for 40%) patients.

Animals↗
PubMed1999

Comparison of iron oxide particles (AMI 227) with a gadolinium complex (Gd-DOTA) in dynamic susceptibility contrast MR imagings (FLASH and EPI) for both phantom and rat brain at 1.5 Tesla.

The goal of the study was to compare, in phantom and normally perfused rat brain tissue, a superparamagnetic iron oxide particle-based contrast agent (AMI 227) with a low-molecular-weight gadolinium chelate, gadolinium tetraazacyclododecanetetraacetic acid (Gd-DOTA), in two susceptibility contrast magnetic resonance imaging (MRI) modes [fast low-angle shot sequence (FLASH) and echoplanar imaging (EPI)]. A phantom consisting of dilution series of both contrast agents was manufactured. Dilutions were obtained with isotonic serum from the available agent solutions (0.5 mmol Gd/mL Gd-DOTA; 350 mumol Fe/mL AMI 227). Eighteen rats were studied. Contrast agent (0.1 mL) was bolus injected in each rat, and dynamic MRI was performed (first pass of the contrast agent) in rat brain. The doses of AMI 227 injected were extrapolated from the phantom experiment: 0.2 mmol/kg body weight of Gd-DOTA and 7, 14, and 28 mumol Fe/kg body weight of AMI 227 were injected. For both sequences, signal-to-noise ratios (S/N) were measured on each tube of the phantom and on rat brain from each image of the dynamic imaging. S/N was plotted versus contrast dilution (phantom) and versus time (rats). In the FLASH sequence, a well-shaped curve (S/N decrease, S/N peak decrease, S/N increase) of the first pass of the contrast agent was demonstrated for Gd-DOTA and for AMI 227 (7 mumol Fe/kg body weight). In the EPI sequence, a well-shaped curve was demonstrated for Gd-DOTA, and a plateau effect was noted for both concentrations of AMI 227. With the FLASH technique, dynamic susceptibility contrast imaging of rat brain can be performed with very low concentrations of AMI 227 compared with the Gd-DOTA concentration (0.2 mmol Gd/kg body weight) used in clinical practice. This could be of interest in perfusion imaging, because it may allow for first-pass susceptibility imaging after administration of a small volume in a narrow bolus.

Animals↗
PubMed1999

Assessment of iron oxide particles (AMI 227) and a gadolinium complex (Gd-DOTA) in dynamic susceptibility contrast MR imagings (FLASH and EPI) in a tumor model implanted in rats.

The objective of our study was to assess the feasibility of dynamic susceptibility contrast MR technique after bolus injection of SPIO and Gd-DOTA in a tumor model implanted in rats. Tumors were subcutaneously implanted in 24 rats. A FLASH sequence and EPI were evaluated. Different doses of AMI 227 and Gd-DOTA were assessed. Mean signal intensity vs. time curves were plotted. Well-shaped curves of the first pass of the contrast agent were only obtained with Gd-DOTA. According to these results it appears difficult to assess tumor blood volume with USPIO dynamic susceptibility contrast imaging.

Animals↗
PubMed1999

Stable Escherichia coli-Clostridium acetobutylicum shuttle vector for secretion of murine tumor necrosis factor alpha.

Recombinant plasmids were constructed to secrete mouse tumor necrosis factor alpha (mTNF-alpha) from Clostridium acetobutylicum. The shuttle plasmids contained the clostridial endo-beta1, 4-glucanase (eglA) promoter and signal sequence that was fused in frame to the mTNF-alpha cDNA. The construction was first tested in Escherichia coli and then introduced in C. acetobutylicum DSM792 by electroporation. Controls confirmed the presence and stability of the recombinant plasmids in this organism. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and an in vitro cytotoxic assay were used to monitor expression and secretion of mTNF-alpha during growth. Significant levels of biologically active mTNF-alpha were measured in both lysates and supernatants. The present report deals with investigations on the elaboration of a gene transfer system for cancer treatment using anaerobic bacteria.

Animals↗
PubMed1998

Colonisation of Clostridium in the body is restricted to hypoxic and necrotic areas of tumours.

The use of gene therapy is one of the most recent molecular strategies for the treatment of cancer. It is essential, however, to have an efficient transfer system by which the desired gene can be delivered to the correct environment. The experiments described in this report investigate apathogenic Clostridium as a possible vector to transfer a specific gene product into the extracellular microenvironment of the tumour which is hypoxic/necrotic in parts, using WAG/Rij rats with transplantable rhabdomyosarcomas as a model. Our data show that Clostridium, after systemic administration of at least 10(7) spores, specifically colonises the hypoxic/necrotic areas of our tumour model, the most efficient species being C. acetobutylicum (NI-4082) and C. oncolyticum. Although spores were also detected in normal tissues for up to 4 weeks, they did not germinate in these tissues. We conclude that it seems likely that these bacteria can be used as a selective transfer system into the extracellular environment of tumours which have hypoxic regions. This strategy would be more tumour-specific than various other strategies that are currently being investigated in anti-cancer gene therapy.

Journal Article↗
PubMed1997

Kinetics of repair in the spinal cord of the rat.

PURPOSE: Split dose experiments were carried out with two 2 Gy fractions per day at intervals ranging from 0.5 to 24 h, in order to investigate both the time to complete repair and the detailed kinetics of repair of sublethal damage in the cervical spine of rats. MATERIALS AND METHODS: Male rats of the WAG/Rij strain were irradiated at 2 Gy/min with 18 MV photons to a length of 18 mm of cervical spinal cord. Four hundred twenty-three rats were irradiated without top-up doses to investigate whether repair was complete by 24 h or whether any slow repair or proliferation occurred up to 50 days after irradiation. Three hundred seventy-nine rats were also irradiated in split dose (2 Gy + delta t + 2 Gy each day) experiments, with intervals of 0.5, 1, 2, 4, 8 and 24 h. The split dose irradiations were followed by a single top-up dose of 15 Gy (producing about half the total damage). RESULTS: Repair was complete by 24 h as the ED50 values were the same at 1, 11 and 50 day intervals for two large fractions, and for 10 fractions in 10 or 50 days. A mono-exponential component of repair of T1/2 = 0.25 (95% CI 0.16-0.48) h was determined by direct analysis using all the data and T1/2 = 0.37 (0.28-0.53) h for the split 2 Gy doses with top-up only. A bi-exponential analysis did not fit better. The presence of a second component was demonstrated graphically, with T1/2 of about 6.5 h but with a wide confidence interval from near 0 to 13 h. However, the 24 h ED50 was significantly different from all ED50s except the 8 h value. Considering all data together, an upper limit of about 7 h could be placed on any long component, or else repair could not be complete by 24 h. DISCUSSION AND CONCLUSIONS: Two components of repair (0.7 and 3.8 h) have been reported by Ang et al. (Ang, K.K., Jiang, G.L., Guttenberger, R., Thames, H.D., Stephens, L.C., Smith, C.D. and Feng, Y. Impact of spinal cord repair kinetics on the practice of altered fractionation schedules. Radiother. Oncol. 25: 287-294, 1992) in the spinal cord of Sprague-Dawley rats. Two components have also been reported by others more recently. The present results could, with its graphical interpretation, agree in principle, but with a shorter fast component and a longer slow component. A slow component of 5.5 h was reported by Ruifrok et al. (Ruifrok, A.C.C., Kleiboer, B.J. and van der Kogel, A.J. Fractionation sensitivity of rat cervical spinal cord during radiation retreatment. Radiother. Oncol. 25: 295-300, 1992) in a related strain of WAG/Rij rats. The possible presence of a slower component than Ang et al.'s 3.8 h might help to explain the four myelopathies observed in the pilot studies for the CHART clinical trial. The presence of the definite fast component (< 0.5 h) could have important consequences when pulsed brachytherapy is used to replace continuous low dose rate irradiation.

Animals↗
PubMed1997

Is pulsed dose rate more damaging to spinal cord of rats than continuous low dose rate?

BACKGROUND AND PURPOSE: Theoretical calculations suggest that pulsed dose-rate irradiation (PDR) should have approximately the same effectiveness as continuous low dose-rate (CLDR) when the same total dose is given in the same overall time, unless large doses per pulse (> 2 Gy) are used and/or non-exponential or very short half-times of repair (< 0.5 h) are present in the irradiated tissues. However, few animal experiments have been reported to test this theory, and some of them gave contradictory results. We have carried out experiments to determine whether PDR irradiation of 18 mm of cervical spinal cord in the rat was more or less effective than CLDR at 0.5-1 Gy/h, when the overall average dose rate during each day of PDR was close to the overall CLDR average dose rate. MATERIALS AND METHODS: PDR was simulated at a within-pulse dose rate of 4 Gy/h by filtered 18 MV X-rays from a linear accelerator. Two PDR schedules were used, 0.69 Gy at 1 h repetition (9 pulses per day) and 2 Gy at 3 h repetition (4 pulses per day), with overnight intervals of 16 and 15 h, respectively. The CLDR was delivered from iridium-192 wires in two concentric rings around a collar designed to fit the necks of rats so that they could eat and drink during the 72 h that was always the duration of the CLDR. Dose rate was then proportional to total CLDR dose. A range of doses was used to obtain dose response-curves, with a 15 Gy top-up dose (at 2 Gy/min, HDR) given on the day after the end of the PDR or CLDR irradiations. Animals were observed for at least 9 months to see whether fore-limb myelopathy developed. A total of 6-8 rats was irradiated per dose point, in two sets of experiments at an interval of 12 months. RESULTS: A set of 2 Gy fractions (at HDR) given daily, followed by the same top-up dose of 15 Gy at HDR, was available from a previous experiment for planning. Its ED50 was 61.2 Gy. The ED50 values found for the PDR schedules with 2 Gy at 3 h and 0.69 Gy at 1 h were 59.9 and 60.2 Gy, respectively. These were just 2% more effective than the daily HDR fractions, similar to expectations from theory if two components of repair are present. However, the CLDR irradiations resulted in no myelopathy even after doses up to 68 Gy at 0.94 Gy/h.. Thus PDR over 7 days (not at nights) appears to be more effective than CLDR over 3 days, with an effective dose-modifying factor of at least 1.1 to 1.17. DISCUSSION AND CONCLUSIONS: Reasons for this absence of effect with CLDR in these experiments are discussed, the most likely explanation being that a substantial component of repair with very short T1/2 (< 0.5 h) was present in spinal cord of these rats. There is evidence from other experiments elsewhere and in our laboratory for such a fast component of repair.

Animals↗
PubMed1993

Radiation response of mouse lip mucosal epithelium: a cell kinetic study.

Changes in the cell proliferation kinetics of the epithelium of mouse lip mucosa have been assessed after local irradiation with a single dose of 18 Gy of 60Co gamma-rays. By the fifth day after irradiation, two distinct sub-populations of epithelial cells could be discerned. The larger of the two populations consisted of cells exhibiting varying degrees of radiation-induced damage, and the smaller population was composed of cells of normal size and appearance, intermingled between the radiation-damaged cells. There was a progressive decline in the epithelial cell density with time after irradiation, and focal denudation was seen after 11 days. Cell colonies were evident in the remnants of the epithelium by day 7. Degenerate cells could be identified in the basal layer of the mucosal epithelium, both before and after irradiation. The proportion of degenerate cells was increased 5 days after irradiation with the maximum number, approximately 3.6% being counted on days 7 and 8. In the first 2 days after irradiation, there was a reduction in the labelling index (LI) of basal cells in the epithelium. This was followed by recovery to control values on day 3. The LIs of both the radiation-damaged cells and those with a normal appearance remained relatively constant between days 5 and 11, at approximately 10 and approximately 60%, respectively. The LI of basal cells in the cell colonies was very high (approximately 70%). The estimated turnover time (TT) for the basal cell population with a normal appearance and for those in cell colonies (groups of normal cells with a cord length > or = 10 cells), was extremely short < 1 day. There was some fluctuation in TT values for basal cells exhibiting radiation-induced damage, with the shortest value (approximately 3 days) at 7 and 8 days after irradiation. It was concluded from the cell kinetic data that repopulation of the lip mucosal epithelium started between 3 and 5 days after irradiation and the overall response of the mucosa to irradiation was consistent with that predicted by a hierarchical model of cell proliferative organization.

Animals↗
PubMed1993

Different immobilization procedures during irradiation influence the estimation of alpha/beta ratios in mouse lip mucosa.

In previous experiments an anaesthetic gas mixture of enflurane (Ethrane, Abbott, Belgium) and oxygen has been used in our department to position mice for local irradiation. The development of a new immobilization method allowed the investigation of possible dose modifying effects of enflurane with different gases as carrier on the radiation response of mouse lip mucosa. The effect of different immobilization procedures on single dose and fractionated irradiations was examined. The experiments were compared on the basis of the dose associated with 50% incidence of lower lip desquamation (ED50 +/- 95% CI). When mice were breathing air the ED50 value following single dose irradiation was 20.0 (19.6 to 20.5) Gy. For mice receiving an anaesthetic gas mixture of enflurane and oxygen the ED50 was decreased significantly to 17.5 (17.2 to 17.8) Gy, indicating a sensitizing effect of the anaesthetic mixture by a factor of 1.14. The impact of different experimental set-ups on the fractionation sensitivity has been assessed. In order to estimate alpha/beta ratios in different treatment conditions two and ten fraction experiments were performed, additionally to the single dose irradiations. Dose modification factors were 1.09 for two fractions and 0.97 for the ten fraction experiment. This varying dose modification leads to a pronounced shift in alpha/beta ratios (estimated by "direct analysis" and graphically illustrated with a Fe-plot). For air breathing animals an alpha/beta ratio of 16.4 (14.5 to 18.9) Gy was estimated by direct analysis, whereas for the enflurane/oxygen anaesthesia 8.7 (7.3 to 10.2) Gy were calculated. Both these data sets were adequately described with the linear-quadratic formalism, as was shown with Tucker's analysis. The sensitizing effect of oxygen alone in single dose irradiations (DMF: 1.07) suggests moderate physiological hypoxia in mouse lip mucosa. The present data emphasize the effect of different immobilization procedures on the estimation of alpha/beta ratios, especially when large fraction sizes are involved. Data from experiments involving large fraction sizes should be avoided in the estimation of repair parameters. Further experimental work has to be carried out to elucidate the possible dose modifying effects of anaesthetic agents in clinical practice, e.g. for infants and for patients undergoing intraoperative radiotherapy.

Anesthesia, Inhalation↗
PubMed1992

The influence of neonatal thymectomy on the development of radiation myelopathy in rats.

To investigate the possible contribution of cellular immunity in the development of radiation injury of the central nervous system, Wag/Rij rats were thymectomized at birth and irradiated to the cervical spinal cord at the age of 3 months. At the time of paralysis or at the end of the follow-up period (when rats were 1-year-old) the animals were sacrificed and the mediastinum was examined histologically. In 95% of the neonatally thymectomized animals no thymus was left. These rats showed a firm impairment of the cellular immunity, as they had a 40% reduction of the T-lymphocytes in the spleen, and a 70% reduction of the mixed lymphocyte reaction, compared to age-matched controls. Both single dose and two-fraction irradiation experiments were performed. No modification of the latency time to develop paralysis was observed comparing thymectomized and age-matched controls. The incidence of foreleg paralysis after cervical spine irradiation (single dose or two-fraction) was identically distributed in the follow-up period for both neonatally thymectomized and control Wag/Rij rats. The ED50 value derived in the single dose experiments was 20.3 Gy for the control animals, and 20.9 Gy for thymectomized rats, and in the two fraction experiments 29 Gy for controls and 29.6 Gy for thymectomized rats. None of these differences are significant. It appears that neonatal thymectomy, in spite of its firm suppression of the cellular immunity, has no major influence on the development of radiation myelopathy in rats.

Animals↗
PubMed1991

Estimation of repair parameters in mouse lip mucosa during continuous and fractionated low dose-rate irradiation.

The present study investigated the effect of fractionated low dose-rate (FLDR) treatments in mouse lip mucosa, a typically early reacting tissue. The relation between dose-rate and fractionation effect has been assessed with various interfraction intervals and dose-rates. A fixed overall treatment time of 10 h has been used for the present continuous and fractionated irradiation experiments with corresponding dose-rates of 3.1-84 Gy/h. Sophisticated mathematical models are now available to estimate repair parameters from data derived with different fraction numbers, fraction sizes and dose-rates. These formulas, allowing the calculations of isoeffect relationships are based on the incomplete repair model and assume that repair can operationally be described by a monoexponential function. A further assumption of these models is that repair of sublethal damage follows the same kinetics during irradiation and between fractions. The present FLDR experiments with small interfraction spacing were performed to investigate the validity of these assumptions and consequently the applicability of the models. In addition, it has been assessed whether the experimental approach of investigating repair kinetics as such [high dose-rate (HDR) split-course vs. continuous low dose-rate (CLDR) or FLDR] influences the estimation of these parameters, as has been suggested from the analysis of in vitro studies. Using the mucosal desquamation endpoint, virtually identical repair parameters have however been estimated with different approaches (alpha/beta = 14.1-18.2 Gy, T1/2 = 28-37 min). The available isoeffect models seem to be applicable to the present experimental data and might after further experimental tests also involving late reacting tissues, be a useful tool for clinical isoeffect calculations.

Animals↗
PubMed1991

Effect of age on the radiation-induced repopulation in mouse lip mucosa.

The acute macroscopic radiation reactions in mouse lip mucosa were used as a biological model to evaluate the influence of aging on the radiosensitivity and more specifically on the repopulation capacity after irradiation of rapidly proliferating epithelial tissues. No difference in the mucosa response after single dose irradiations was observed for animals ranging between one and twelve months of age. There was a trend for decreased radiosensitivity of the lip mucosa comparing 18 months old (early-senescence) with young adult mice. The repopulation experiments involved two equal sized radiation doses delivered with an interval of ten days. Again, in all age-groups, not only was the 50% incidence-dose for mucosa desquamation similar, but also the full biphasic course of radiation reactions. These data therefore demonstrate that the capacity of the lip mucosa basal cells to restore the radiation damage was not modified by the phenomenon of aging.

Age Factors↗
PubMed1989

Repair kinetics as a determining factor for late tolerance of central nervous system to low dose rate irradiation.

The effect of continuous irradiation, delivered at four different dose rates (107.6, 14.7, 3.9 and 2 Gy.h-1) has been investigated using the rat cervical spinal cord biological system. The endpoint was the induction of foreleg paralysis at 9 months which corresponds, as has been described before, to white matter necrosis. Paralysis occurring in 50% of the animals was taken as the isoeffect, and the ED50 (radiation dose leading to paralysis in 50% of the animals) was calculated by probit analysis. There was a constant increase in the ED50 with the decrease in the dose rate, resulting from the repair of sublethal damage (SLD) occurring during irradiation. A comparison was made with the previously published results of high dose rate (100-120 Gy.h-1) fractionated irradiations (2, 4 and 10 fractions). alpha/beta (1.6 Gy for the pooled fractionation and dose rate data) and the half-time of SLD repair (82 min) were derived.

Animals↗
PubMed1989

Effects of high dose intraperitoneal cytosine arabinoside on the radiation tolerance of the rat spinal cord.

The effect of intraperitoneal high dose (9 g/kg) Cytosine Arabinoside (Ara-C) on the early delayed radiation response of the rat cervical spinal cord has been studied. When given 2 hrs before irradiation, systemically administered Ara-C significantly reduces the isoeffect doses for the induction of paralysis due to white matter necrosis by a factor of approximately 1.2 for both a single irradiation treatment and for a two fraction irradiation with 24 hr interval. No effect on the latency time to develop paralysis was recorded.

Animals↗
PubMed1989

Kinetics of sublethal damage recovery in mouse lip mucosa comparing low and high-LET radiation.

The effects of d(50) + Be neutrons on the lip mucosa in mice were investigated as a model of early effects. The biological endpoint eas the incidence of desquamation in the lower lip after selective irradiation of the snout of the animals. ED 50 (dose leading to desquamation in 50% of the animals) were calculated by probit analysis. Fractionated (two, four and ten fractions) and protracted (43.5, 11.5 and 0.88 Gy.h-1) irradiations have been carried out. Results were analysed using the mathematical method of Dale. An alpha/beta of 39.6 Gy and a t 1/2 of recovery of sublethal damage of 47 min have been derived. These results have been compared to data previously obtained with cobalt-60 gamma rays. Using the same mathematical approach, and comparing similar fractionated and protracted experiments, an alpha/beta of 7.4 Gy and a t 1/2 of recovery of 47 min have been calculated. There was no significant difference in the repair kinetics after irradiations with gamma rays or d(50) + Be neutrons.

Animals↗