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R Huiskamp

Publications and source records attributed to R Huiskamp.

At least 37 records · Page 2Linked to original sources
PubMed1994

Clinical phase-I study of Na2B12H11SH (BSH) in patients with malignant glioma as precondition for boron neutron capture therapy (BNCT).

PURPOSE: Within the European collaboration on boron neutron capture therapy (BNCT), a clinical Phase I study is being carried out to establish BNCT as an alternative treatment modality for malignant glioma (WHO III/IV). Data about the pharmacokinetics, biodistribution and toxicity of the boron compound Na2B12H11SH (BSH) are of great importance to avoid radiation damage of healthy tissue and to deliver a sufficient radiation dose. METHODS AND MATERIALS: Twenty four patients suffering from a glioblastoma multiforme entered the study to date, infused with a maximum concentration of up to 50 mg BSH/kg. Boron concentration measurements in tissues, urine, and blood were carried out, using inductively coupled plasma-atomic spectroscopy (ICP-AES) and quantitative neutron capture radiography (QNCR). A cross-calibration of these boron determination techniques was carried out. RESULTS: In tumor tissue, confirmed by histopathology of small biopsies, we found a consistently high but heterogeneous boron uptake. Necrotic parts contain much lower amounts of boron; normal brain tissue has shown no significant uptake. In skin, bone, muscle, and dura mater only small amounts of boron were found. In blood samples, we found biphasic kinetics, but with variations of the half-lives from patient to patient. The compound is mainly excreted through the urine, but an additional entero-hepatic pathway can be demonstrated. Systematic investigations revealed no toxic side effect of the intravenously administered BSH. Comparable data were obtained by using ICP-AES and QNCR for boron concentration measurements. CONCLUSION: Taking into account the radiobiological considerations of the neutron beam source, we found promising facts that BNCT could be a useful irradiation method for highly malignant brain tumors. Favorable amounts of the boron compound BSH were found in tumor tissue, whereas healthy brain tissue has shown no significant uptake.

Aged↗
PubMed1994

Pharmacokinetics in melanoma-bearing mice of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a candidate compound for boron neutron capture therapy.

Blood pharmacokinetics and tissue distribution of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a boron carrier with postulated melanin-seeking properties for boron neutron capture therapy, were determined in C57/BL mice with subcutaneous pigmented or non-pigmented B16 melanomas. Borocaptate sodium (BSH) was used as a boron compound without melanin-seeking properties in a comparative biodistribution study in the same animal tumour models. Administration of single doses showed that BPTU was retained better in the pigmented B16 tumour than in the non-pigmented variant. BPTU was found in large concentrations in kidney and liver. Brain boron was approximately 10-fold lower than tumour boron. On a molar basis, BPTU demonstrated higher affinity for B16 tumours than BSH. Owing to solubility limits, tumour boron concentrations in this mouse study were too low for effective application of BNCT. However, the high tumour-to-blood and tumour-to-normal tissues ratios indicate that, with appropriate formulation, BPTU could be a promising candidate for clinical BNCT.

Animals↗
PubMed1994

A comprehensive PC-based computer model for microdosimetry of BNCT.

A computer model is described that performs microdosimetric calculations of the radiation dose delivered to tumour and normal tissue in boron neutron capture therapy (BNCT) by simulating capture reactions in a predefined three-dimensional space. The role of intracellular boron distributions and cellular dimensions on the radiation dose in clinical and experimental BNCT has been studied using a PC-based computer model. In order to calculate the radiation dose to low boron uptake cells, the extent of irradiation by boron containing adjacent cells (cross fire) is also dealt with. Radiation doses from boron and nitrogen neutron capture are converted to a biological effect by means of relative individual ion track segment efficacies, based on linear energy transfer along the particle track. A good correlation was found after comparing predicted values with previously published experimental data. A number of examples is given to illustrate the program's features.

Boron Neutron Capture Therapy↗
PubMed1994

Radiosensitivity of testicular cells in the prepubertal mouse.

The effects of total-body X irradiation on the prepubertal testis of the CBA/P mouse have been studied. At either day 14 or day 29 post partum male mice were exposed to single doses of X rays ranging from 1.5-6.0 Gy. At 1 week after irradiation the repopulation index method was used to study the radiosensitivity of the spermatogonial stem cells. A D0 value of 1.8 Gy was determined for the stem cells at day 14 post partum as well as for the stem cells at day 29 post partum, indicating that the radiosensitivity of the spermatogonial stem cells in the prepubertal mouse testis is already comparable to that observed in the adult mouse. One, 2 or 3 weeks after irradiation total cell numbers per testis of Sertoli cells, Leydig cells, mesenchymal cells, macrophages, myoid cells, lymphatic endothelial cells, endothelium and perivascular cells were determined using the disector method. The Sertoli cells and interstitial cell types appeared to be relatively radioresistant during the prepubertal period. No significant changes in plasma testosterone levels were found, indicating that there is no Leydig cell dysfunction after exposure to doses up to 6 Gy during the prepubertal period. Taken together, the radioresponse of the prepubertal mouse testis is comparable to that of the adult mouse testis.

Age Factors↗
PubMed1993

Selectivity of boron carriers for boron neutron capture therapy: pharmacological studies with borocaptate sodium, L-boronophenylalanine and boric acid in murine tumors.

Borocaptate sodium (BSH) and L-boronophenylalanine (L-BPA) are two boron carriers used for boron neutron capture therapy (BNCT) in the treatment of glioblastoma and melanoma, respectively. The suitability of these two compounds was evaluated on the basis of pharmacokinetic studies aiming at characterizing their biodistribution, tumor uptake and tumor selectivity. Boric acid was also used as a reference compound since it is nonselective and relatively freely diffusible. The compounds were investigated in two tumor models, a B16 pigmented melanoma and the RIF1 sarcoma. Mice were sacrificed after different boron doses at various post-injection times and tissue and plasma levels measured using inductively coupled plasma atomic emission spectroscopy (ICP-AES). The proposed minimum effective tumor boron concentration of 15 ppm was achieved in both tumor models for the three compounds tested, although only for L-BPA in the melanoma was this achieved when tumor-plasma ratios were above 1. In the RIF1 model, maximum tumor concentrations of 44 and 31 ppm B were reached after administration of 50 micrograms B/g body weight for boric acid and BSH, respectively. After administration of 12.5 micrograms B/g of L-BPA, maximum concentrations of 15 and 21 ppm were found in the RIF1 and B16 models, respectively. Tumor-plasma ratios (TPR) for BSH remained close to or below unity at all times studied in both tumors. Brain levels of BSH were very low, however, leading to tumor-brain ratios markedly greater than 1 at all times. L-BPA and boric acid showed TPR values above unity in both tumor models, reaching 3.2 in B16.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Quantitative neutron capture radiography for boron in biological specimens.

Track-etch detectors made of cellulose nitrate (LR 115, Kodak Pathé) and polycarbonate (CR 39, Pershore Mouldings Ltd) were compared regarding sensitivity and background when used as detectors for boron determination in biological samples. Measurements were made on two kinds of sample, cryosectioned biological tissue, and liquid samples deposited directly on the detector surface as microdroplets. The CR 39 films were pretreated or washed before irradiation. When cryosectioned tissue was used, measurements were made with and without the inclusion of Mylar foils between the samples and the detectors. Foil thicknesses used were 2 microns in the case of LR 115 and 2, 4, and 6 microns in the case of CR 39. All samples were irradiated with a thermal-neutron fluence of 5 x 10(12) neutrons cm-2 at the thermal-neutron facility in Studsvik, Sweden. The use of a Mylar foil generally suppressed the background tracks relative to the tracks from the 10B disintegration. No difference in resolution between CR 39 and LR 115 was observed. Pretreatment of the CR 39 resulted in an improved sensitivity of detection but the detector became saturated at 0.25 parts per million of 10B. The background was found to be lower in the pretreated detector.

Blood↗
PubMed1993

Postnatal development of testicular cell populations in mice.

The postnatal development of body and testis weight and the size of the testicular cell populations were studied in CBA mice up to day 52 post partum. The body weight increased from 1.3 g at day 1 to 22.5 g at day 52. Over the same interval the testis weight showed a faster increase from about 1 mg to almost 60 mg. Spermatogenesis was found to be complete by day 35. The numbers of A spermatogonia, Sertoli cells, Leydig cells, mesenchymal cells, macrophages, myoid cells, lymphatic endothelial cells, endothelial cells and perivascular cells per testis were studied from day 3 to day 50, using the dissector method. The number of A spermatogonia increased from 0.2 x 10(5) at day 3 to 6.5 x 10(5) at day 21 and remained more or less constant thereafter. The Sertoli cell population increased during the first three weeks after birth to reach the adult level of approximately 18 x 10(5) cells per testis. In the interstitium the Leydig cells showed a sharp increase between days 11 and 31 followed by a small decrease to ultimately 9 x 10(5) cells per testis. The Leydig cells formed 8% of the total number of interstitial cells per testis at day 11, increasing to 30% at day 50. The number of mesenchymal cells did not change until day 36, decreasing thereafter from about 2.5 x 10(5) to 1 x 10(5) cells per testis at day 50. However, the percentage of the total number of interstitial cells that were mesenchymal cells decreased from 59% to 4%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Differential effects of fractionated X irradiation on mouse spermatogonial stem cells.

The response of spermatogonial stem cells to fractionated X irradiation was studied in the various stages of the spermatogenic cycle of the CBA mouse. Fractionated doses of 2 + 2, 1 + 3, and 3 + 1 Gy with a 24-h interval between the doses were compared with a single dose of 4 Gy. The numbers of undifferentiated spermatogonia present 10 days after (the second) irradiation were taken as a measure of stem cell survival. Twenty-four hours after the first irradiation a sensitization was observed that was found to be stage-dependent. The greatest sensitization occurred in that part of the spermatogonial stem cell population that was in stages X-I during the first irradiation, i.e., the part that is stimulated to proliferate or actively proliferating at that time. In stages that were quiescent during the first irradiation (VI-VII), fractionation did not influence the response. Therefore, only the spermatogonial stem cells that are initially radioresistant become sensitized 24 h after irradiation. When two unequal doses (3 + 1 Gy or 1 + 3 Gy) are given, damage correlates with the size of the second dose, indicating that priming doses of 1 and 3 Gy are both capable of inducing the sensitizing effect.

Animals↗
PubMed1993

Large animal normal tissue tolerance using an epithermal neutron beam and borocaptate sodium.

Irradiation of the canine head following intravenous Na2B12H11SH (BSH) administration has provided useful information concerning the tolerance of skin and brain to the resultant complex form of irradiation. The effect of the boron capture reaction in skin and brain has provided estimates of the influence of the microscopic dosimetry involved. Dogs irradiated with the epithermal beam alone provided valuable insight into the relative biological effectiveness (RBE) of the fast neutron component (> 10 keV) of the epithermal beam. When compared with literature values for X-rays for the occurrence of skin necrosis in dogs, an RBE of 4.5 was derived. Previous pharmacokinetic data concerning the distribution of Na2B12H11SH (BSH) to blood and brain has been used to obtain input parameters for computer models of the microvasculature of the brain. Monte Carlo computer models were used to simulate the microscopic distribution of BSH in the normal brain. The term compound factor describes the product of the microscopic boron fission fragment dose hitting the nucleus and the relative biologic effectiveness divided by the macroscopic equilibrium dose of the boron reaction in the tissue of interest. The computed compound factor for Na2B12H11SH (BSH) in normal brain was 0.37. This factor agreed very well with the value of 0.32 obtained for the brain necrosis with the dog irradiations. The compound factor for the dog's skin was experimentally derived from the dog experiments and was equal to 0.5.

Animals↗
PubMed1992

Effects of X-irradiation and adriamycin on quiescent and proliferating cells of the seminal vesicle in the castrated mouse.

The sensitivity of resting and proliferating cells of the seminal vesicle to X-irradiation and adriamycin has been investigated. Stimulation with testosterone propionate (250 micrograms/day) was started 11 days after castration in BALB/c mice. X-rays (2.5-7.5 Gy total body irradiation) and intraperitoneal injections of adriamycin (4-16 mg/kg body weight) were administered at various times before or after induction of proliferation by testosterone injection. The DNA contents and the weights of the seminal vesicles were determined at 4 days after the start of stimulation. A Do for X-rays of about 10 Gy was found for the seminal vesicle epithelium. For both X-irradiation and adriamycin no significant differences in sensitivity were observed between quiescent (Go) and proliferating (G1; S) seminal vesicle cells.

Animals↗
PubMed1992

The effects of graded doses of 1 MeV fission neutrons or X rays on the murine hematopoietic stroma.

The acute radiosensitivity in vivo of the murine hematopoietic stroma for 1 MeV fission neutrons or 300 kVp X rays was determined. Two different assays were used: (1) an in vitro clonogenic assay for fibroblast precursor cells (CFU-F) and (2) subcutaneous grafting of femora or spleens. The number of stem cells (CFU-S) or precursor cells (CFU-C), which repopulated the subcutaneous implants, was used to measure the ability of the stroma to support hemopoiesis. The CFU-F were the most radiosensitive, and the survival curves after neutron and X irradiation were characterized by D0 values of 0.75 and 2.45 Gy, respectively. For regeneration of CFU-S and CFU-C in subcutaneously implanted femora, D0 values of 0.92 and 0.84 Gy after neutron irradiation and 2.78 and 2.61 Gy after X irradiation were found. The regeneration of CFU-S and CFU-C in subcutaneously implanted spleens was highly radioresistant as evidenced by D0 values of 2.29 and 1.49 Gy for survival curves obtained after neutron irradiation, and D0 values of 6.34 and 4.85 Gy after X irradiation. The fission-neutron RBE for all the cell populations was close to 3 and varied from 2.77 to 3.28. The higher RBE values observed for stromal cells, compared to the RBE of 2.1 reported previously for hemopoietic stem cells, indicate that stromal cells are relatively more sensitive than hemopoietic cells to neutron irradiation.

Animals↗
PubMed1992

The sensitivity of quiescent and proliferating mouse spermatogonial stem cells to X irradiation.

The radiosensitivity of spermatogonial stem cells to X rays was determined in the various stages of the cycle of the seminiferous epithelium of the CBA mouse. The numbers of undifferentiated spermatogonia present 10 days after graded doses of X rays (0.5-8.0 Gy) were taken as a measure of stem cell survival. Dose-response relationships were generated for each stage of the epithelial cycle by counting spermatogonial numbers and also by using the repopulation index method. Spermatogonial stem cells were found to be most sensitive to X rays during quiescence (stages IV-VII) and most resistant during active proliferation (stages IX-II). The D0 for X rays varied from 1.0 Gy for quiescent spermatogonial stem cells to 2.4 Gy for actively proliferating stem cells. In most epithelial stages the dose-response curves showed no shoulder in the low-dose region.

Animals↗
PubMed1992

The sensitivity to X rays of mouse spermatogonia that are committed to differentiate and of differentiating spermatogonia.

In the CBA mouse the radiosensitivity of the undifferentiated spermatogonia that are committed to differentiate was determined by counting their more developed descendants 10 days after graded doses of X rays. Decreasing D0 values were found when these differentiating spermatogonia were derived from undifferentiated spermatogonia that were located in all likelihood in chains of increasing length. In stages IX and X of the epithelial cycle the radiosensitivity of these undifferentiated spermatogonia was characterized by a D0 of 2.2 Gy. This D0 value most likely belongs to the Asingle spermatogonia that form repopulating colonies which give rise to differentiating spermatogonia within the same epithelial cycle. In stages XII/I, where a D0 of 1.0 Gy was found, the dose-response curve is likely dominated by the Apaired spermatogonia present in these stages. In stages III to VII, the Aaligned spermatogonia transforming into A1 spermatogonia determine the radiosensitivity. During this period the D0 decreased from 0.7 to 0.4 Gy. Differentiating A1 to A3 and B spermatogonia had rather similar radiosensitivities of 0.4 to 0.5 Gy.

Animals↗
PubMed1991

Proliferative activity of gonocytes, Sertoli cells and interstitial cells during testicular development in mice.

Developing mouse testis was studied from Day 14 post coitum (p.c.) until Day 35 post partum (p.p.) by [3H]thymidine autoradiography. The gonocytes proliferated actively at Day 14 p.c., the [3H]thymidine labelling index (L.I.) being 7.5%, and were quiescent from Day 16 p.c. up to the first day of life, when spermatogenesis started. The L.I. increased to 20% at Day 2 p.p. The L.I. for the Sertoli cells was approximately 20% before birth. After birth the proliferative activity decreased. After Day 11 p.p., the Sertoli cells showed their typical adult appearance. After Day 17 p.p. no labelled Sertoli cells were observed. The Leydig cells featured a very low proliferative activity up to Day 21 p.p. (L.I. of maximal 1.9%). At Day 29 p.p. there was a peak of 7.4% in L.I., followed by a sharp decrease to 0.35% at Day 35 p.p. The L.I. of mesenchymal cells decreased from 11.4% at Day 14 p.c. to 1.1% at Day 14 p.p. and remained more or less constant thereafter. The proliferative activity of myoid, endothelial and perivascular cells followed a similar course to that of mesenchymal cells, their L.I.s being high before birth (16, 12.5 and 19%, respectively, decreasing until Day 14 p.p. (0.6, 2.0 and 1.2%, respectively) and thereafter being more or less constant. There was an increase in the relative number of Leydig cells from approximately 4% of the total interstitial cell number at Day 14 p.p. to 29.5% at Day 35 p.p. At the same time, the relative number of mesenchymal cells decreased from 55 to 13%. The diameter of the seminiferous tubules showed a peak of 92 microns at Day 16 p.c., decreased to 44 microns at Day 1 p.p. and increased again to 204 microns at Day 33 p.p. These results show that, except for the Leydig cells, the proliferative activity of testicular cell types is highest during the pre- and early postnatal period. The major outgrowth of the Leydig cell population occurs around the fourth week after birth. The results are in accordance with the hypothesis that the mesenchymal cells are the progenitors of Leydig cells.

Animals↗
PubMed1991

The effects of x-irradiation on hematopoietic stem cell compartments in the mouse.

The sensitivity for x-irradiation of a series of hematopoietic stem cell populations has been determined. The most primitive cells identified, cells with marrow-repopulating ability (MRA), showed the highest degree of radioresistance. These MRA cells which generate many secondary day-twelve spleen colony-forming units (MRA[CFU-S-12]) or colony-forming units in culture (MRA[CFU-C]) in the marrow of primary recipients had Do values equal to 1.18 and 1.13 Gy, respectively. The more mature CFU-S-12 had intermediate radiosensitivity (Do = 0.94 Gy), whereas the less primitive CFU-S-7 were the most radiosensitive (Do = 0.71 Gy). The in vitro colony-forming precursor cells (CFU-C) showed low radiosensitivity. These data clearly show that the most primitive hematopoietic stem cell measured is less sensitive to ionizing radiation than generally has been assumed on the basis of measurements on CFU-S-7 or CFU-S-12.

Animals↗
PubMed1989

Active uptake and extravesicular storage of m-iodobenzylguanidine in human neuroblastoma SK-N-SH cells.

Radio-iodinated m-iodobenzylguanidine (MIBG), an analogue of the neurotransmitter norepinephrine (NE), is increasingly used in the diagnosis and treatment of neural crest tumors. Active uptake and subsequent retention of MIBG and NE was studied in human neuroblastoma SK-N-SH cells. Neuron-specific uptake of [125I]MIBG and [3H]NE saturated at extracellular concentration of 10(-6) M and exceeded by 20-30-fold that by passive diffusion alone. A minimum of 50% of accumulated MIBG remained permanently stored but the SK-N-SH cells were incapable of retaining recaptured [3H]NE. [125I]MIBG was displaced from intracellular binding sites by unlabeled MIBG with 10-fold higher potency than by unlabeled NE. MIBG stored in SK-N-SH cells was insensitive to depletion by the inhibitor of granular uptake reserpine (RSP) and was not precipitated in a granular fraction by differential centrifugation. Only few electron-dense granules were found in these cells by electron microscopy. In contrast, MIBG storage in PC-12 pheochromocytoma cells which contained many storage granules, was sensitive to RSP and part of accumulated drug was recovered in a granular fraction. Accordingly, storage of MIBG in the SK-N-SH neuroblastoma cells is predominantly extravesicular and thus essentially different from that of biogenic amines in normal adrenomedullary tissue or in pheochromocytoma tumors, while sharing with these tissues a common mechanism of active uptake.

3-Iodobenzylguanidine↗
PubMed1988

The effect of graded doses of fission neutrons or X rays on the stromal compartment of the thymus in mice.

The effect of irradiation on the supportive role of the thymic stroma in T cell differentiation was investigated in a transplantation model using athymic nude mice and transplanted irradiated thymuses. In this model, neonatal CBA/H mice were exposed to graded doses of whole-body irradiation with fast fission neutrons of 1 MeV mean energy or 300 kVp X rays. The doses used varied from 2.75 up to 6.88 Gy fission neutrons and from 6.00 up to 15.00 Gy X rays at center-line dose rates of 0.10 and 0.30 Gy/min, respectively. Subsequently, the thymus was excised and a thymus lobe was transplanted under the kidney capsule of H-2 compatible nude mice. One and two months after transplantation, the T cell composition of the thymic transplant was investigated using immunohistology with monoclonal antibodies directed to the cell surface differentiation antigens Thy-1, Lyt-1, Lyt-2, MT-4, and T-200. Furthermore, the stromal cell composition of the thymic transplant was investigated with monoclonal antibodies directed to MHC antigens and with monoclonal antibodies defining different subsets of thymic stromal cells. To investigate the reconstitution capacity of the thymic transplant, the peripheral T cell number was measured using flow cytofluorometric analysis of nude spleen cells with the monoclonal antibodies anti-Thy-1, anti-Lyt-2, and anti-MT-4. The results of this investigation show that a neonatal thymus grafted in a nude mouse has a similar stromal and T cell composition as that of a normal thymus in situ. In addition, grafting of such a thymus results in a significant increase of the peripheral T cell number. Irradiation of the graft prior to transplantation has no effects on the stromal and T cell composition but the graft size decreases. This reduction of size shows a linear dose-response curve after neutron irradiation. The X-ray curve is linear for doses in excess of 6.00 Gy. The RBE for fission neutrons for the reduction of the relative thymic graft size to 10% was equal to 2.1. Furthermore, the peripheral T cell number decreases with increasing doses of irradiation given to the graft prior to transplantation. The present data indicate that the regenerative potential of thymic stromal cells is radiosensitive and is characterized by D0 values equal to 2.45 and 3.68 Gy for neutrons and X rays, respectively. In contrast, the ability of the thymic stromal cells to support T cell maturation is highly radioresistant.

Animals↗