Biomedical subjects

Johan Bussink

Publications and source records attributed to Johan Bussink.

17 recordsLinked to original sources

PubMed2006

Microenvironmental transformations by VEGF- and EGF-receptor inhibition and potential implications for responsiveness to radiotherapy.

The microregional distribution and dynamics of tumor cell hypoxia and proliferation are important determinants of tumor aggressiveness and resistance to treatment. Modulation of these elements by biological targeted drugs such as EGFR- and VEGFR-inhibitors may improve the effect of radiotherapy significantly. These combinations are being evaluated in clinical trials and evidence of their effectiveness is accumulating. However, the mechanistic basis of this cooperative effect and the role and behavior of the microregional tumor phenotype under EGF- and VEGF-blockage is poorly understood. Unfolding of these interactions and effects further downstream is necessary to exploit these biological modifiers most profitably to unravel questions such as: (1) can microregional phenotypes be modulated by EGFR- or VEGFR-blockage and how do downstream effects in the signaling pathways relate to these changes? (2) How do the microregional changes induced by EGFR- and VEGF-blockage affect the responsiveness of tumors to ionizing radiation? Answering these questions will improve our understanding of tumor growth related phenotypic transformations at the microregional level and how these can be influenced by modulation of the EGF- and VEGF-signaling pathways. This knowledge can be used to identify and improve therapeutic combinations with the novel biological modifiers and test a variety of biological-based treatment approaches.

Cell Cycle↗

PubMed2006

Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors.

PURPOSE: Hypoxia is one of the reasons for radiation therapy resistance. Positron emission tomography using (18)F-labeled misonidazole ([(18)F]FMISO) is a non-invasive method of imaging tumor hypoxia. Aim of this study was to validate [(18)F]FMISO against the clinically most widely used hypoxic cell marker pimonidazole under different oxygenation conditions. MATERIALS AND METHODS: One human head and neck squamous cell carcinoma (SCCNij3) and two human glioblastoma (E102 and E106) xenograft tumor lines were studied after injection of [(18)F]FMISO and pimonidazole. Control mice were compared with a second group breathing carbogen to reduce tumor hypoxia and with a third group with clamped tumors to increase hypoxia. Tumor sections were analyzed on a phosphor imaging system and consecutively stained immunohistochemically (IHC) for visualization of pimonidazole. Pixel-by-pixel analysis was performed and the hypoxic fraction, obtained after segmentation of the pimonidazole signal, was related to the mean optical density of [(18)F]FMISO and pimonidazole. RESULTS: A moderate pixel-by-pixel correlation between [(18)F]FMISO autoradiography and pimonidazole IHC was found for the control tumors, after carbogen breathing and after clamping for SCCNij3. For E102 and E106, mean signal intensities for pimonidazole significantly decreased after carbogen breathing and increased after clamping, mean [(18)F]FMISO signal intensities increased significantly after clamping and a significant correlation between the hypoxic fractions and the mean [(18)F]FMISO signal intensities was found. CONCLUSIONS: [(18)F]FMISO autoradiography and pimonidazole immunohistochemistry can both be used to visualize treatment induced changes in tumor hypoxia. However, the response to these modifications differs widely between xenograft tumor lines.

Animals↗

PubMed2006

Effect of carbogen breathing on the radiation response of a human glioblastoma xenograft: analysis of hypoxia and vascular parameters of regrowing tumors.

BACKGROUND AND PURPOSE: The aim of these experiments was to study the relationship between the previously demonstrated efficacy of carbogen breathing on tumor oxygenation status and the response to radiation assessed by a growth delay assay. This study was also developed to investigate the microenvironmental changes caused by combined treatment compared to irradiation only in regrowing tumors. MATERIAL AND METHODS: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without carbogen breathing. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after immunohistochemical staining. Tumor growth delay was monitored for up to 120 days after treatment. RESULTS: In general, there was no benefit of combined treatment. However, a small subgroup with good response to combined radiation and carbogen treatment was identified showing little hypoxia and mainly necrosis in the regrowing tumors. These microenvironmental characteristics were not seen in tumors of the other treatment groups. CONCLUSION: The observations suggest that a subgroup of patients, who could potentially benefit from the combined carbogen and radiation treatment, might be identified. However, the heterogeneous response to treatment illustrates the need for selection of patients before start of treatment.

Animals↗

PubMed2006

Dynamics of hypoxia, proliferation and apoptosis after irradiation in a murine tumor model.

Proliferation and hypoxia affect the efficacy of radiotherapy, but radiation by itself also affects the tumor microenvironment. The purpose of this study was to analyze temporal and spatial changes in hypoxia, proliferation and apoptosis after irradiation (20 Gy) in cells of a murine adenocarcinoma tumor line (C38). The hypoxia marker pimonidazole was injected 1 h before irradiation to label cells that were hypoxic at the time of irradiation. The second hypoxia marker, CCI-103F, and the proliferation marker BrdUrd were given at 4, 8 and 28 h after irradiation. Apoptosis was detected by means of activated caspase 3 staining. After immunohistochemical staining, the tumor sections were scanned and analyzed with a semiautomatic image analysis system. The hypoxic fraction decreased from 22% in unirradiated tumors to 8% at both 8 h and 28 h after treatment (P < 0.01). Radiation did not significantly affect the fraction of perfused vessels, which was 95% in unirradiated tumors and 90% after treatment. At 8 h after irradiation, minimum values for the BrdUrd labeling index (LI) and maximum levels of apoptosis were detected. At 28 h after treatment, the BrdUrd labeling and density of apoptotic cells had returned to pretreatment levels. At this time, the cell density had decreased to 55% of the initial value and a proportion of the cells that were hypoxic at the time of irradiation (pimonidazole-stained) were proliferating (BrdUrd-labeled). These data indicate an increase in tumor oxygenation after irradiation. In addition, a decreased tumor cell density without a significant change in tumor blood perfusion (Hoechst labeling) was observed. Therefore, it is likely that in this tumor model the decrease in tumor cell hypoxia was caused by reduced oxygen consumption.

Animals↗

PubMed2005

Observer variation in target volume delineation of lung cancer related to radiation oncologist-computer interaction: a 'Big Brother' evaluation.

BACKGROUND AND PURPOSE: To evaluate the process of target volume delineation in lung cancer for optimization of imaging, delineation protocol and delineation software. PATIENTS AND METHODS: Eleven radiation oncologists (observers) from five different institutions delineated the Gross Tumor Volume (GTV) including positive lymph nodes of 22 lung cancer patients (stages I-IIIB) on CT only. All radiation oncologist-computer interactions were recorded with a tool called 'Big Brother'. For each radiation oncologist and patient the following issues were analyzed: delineation time, number of delineated points and corrections, zoom levels, level and window (L/W) settings, CT slice changes, use of side windows (coronal and sagittal) and software button use. RESULTS: The mean delineation time per GTV was 16 min (SD 10 min). The mean delineation time for lymph node positive patients was on average 3 min larger (P = 0.02) than for lymph node negative patients. Many corrections (55%) were due to L/W change (e.g. delineating in mediastinum L/W and then correcting in lung L/W). For the lymph node region, a relatively large number of corrections was found (3.7 corr/cm2), indicating that it was difficult to delineate lymph nodes. For the tumor-atelectasis region, a relative small number of corrections was found (1.0 corr/cm2), indicating that including or excluding atelectasis into the GTV was a clinical decision. Inappropriate use of L/W settings was frequently found (e.g. 46% of all delineated points in the tumor-lung region were delineated in mediastinum L/W settings). Despite a large observer variation in cranial and caudal direction of 0.72 cm (1 SD), the coronal and sagittal side windows were not used in 45 and 60% of the cases, respectively. For the more difficult cases, observer variation was smaller when the coronal and sagittal side windows were used. CONCLUSIONS: With the 'Big Brother' tool a method was developed to trace the delineation process. The differences between observers concerning the delineation style were large. This study led to recommendations on how to improve delineation accuracy by adapting the delineation protocol (guidelines for L/W use) and delineation software (double window with lung and mediastinum L/W settings at the same time, enforced use of coronal and sagittal views) and including FDG-PET information (lymph nodes and atelectasis).

Aged↗

PubMed2005

Reduction of observer variation using matched CT-PET for lung cancer delineation: a three-dimensional analysis.

PURPOSE: Target delineation using only CT information introduces large geometric uncertainties in radiotherapy for lung cancer. Therefore, a reduction of the delineation variability is needed. The impact of including a matched CT scan with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and adaptation of the delineation protocol and software on target delineation in lung cancer was evaluated in an extensive multi-institutional setting and compared with the delineations using CT only. METHODS AND MATERIALS: The study was separated into two phases. For the first phase, 11 radiation oncologists (observers) delineated the gross tumor volume (GTV), including the pathologic lymph nodes of 22 lung cancer patients (Stages I-IIIB) on CT only. For the second phase (1 year later), the same radiation oncologists delineated the GTV of the same 22 patients on a matched CT-FDG-PET scan using an adapted delineation protocol and software (according to the results of the first phase). All delineated volumes were analyzed in detail. The observer variation was computed in three dimensions by measuring the distance between the median GTV surface and each individual GTV. The variation in distance of all radiation oncologists was expressed as a standard deviation. The observer variation was evaluated for anatomic regions (lung, mediastinum, chest wall, atelectasis, and lymph nodes) and interpretation regions (agreement and disagreement; i.e., >80% vs. <80% of the radiation oncologists delineated the same structure, respectively). All radiation oncologist-computer interactions were recorded and analyzed with a tool called "Big Brother." RESULTS: The overall three-dimensional observer variation was reduced from 1.0 cm (SD) for the first phase (CT only) to 0.4 cm (SD) for the second phase (matched CT-FDG-PET). The largest reduction in the observer variation was seen in the atelectasis region (SD 1.9 cm reduced to 0.5 cm). The mean ratio between the common and encompassing volume was 0.17 and 0.29 for the first and second phases, respectively. For the first phase, the common volume was 0 in 4 patients (i.e., no common point for all GTVs). In the second phase, the common volume was always >0. For all anatomic regions, the interpretation differences among the radiation oncologists were reduced. The amount of disagreement was 45% and 18% for the first and second phase, respectively. Furthermore, the mean delineation time (12 vs. 16 min, p<0.001) and mean number of corrections (25 vs. 39, p<0.001) were reduced in the second phase compared with the first phase. CONCLUSION: For high-precision radiotherapy, the delineation of lung target volumes using only CT introduces too great a variability among radiation oncologists. Implementing matched CT-FDG-PET and adapted delineation protocol and software reduced observer variation in lung cancer delineation significantly with respect to CT only. However, the remaining observer variation was still large compared with other geometric uncertainties (setup variation and organ motion).

Aged↗

PubMed2005

Hypoxic cell turnover in different solid tumor lines.

PURPOSE: Most solid tumors contain hypoxic cells, and the amount of tumor hypoxia has been shown to have a negative impact on the outcome of radiotherapy. The efficacy of combined modality treatments depends both on the sequence and timing of the treatments. Hypoxic cell turnover in tumors may be important for optimal scheduling of combined modality treatments, especially when hypoxic cell targeting is involved. METHODS AND MATERIALS: Previously we have shown that a double bioreductive hypoxic marker assay could be used to detect changes of tumor hypoxia in relation to the tumor vasculature after carbogen and hydralazine treatments. This assay was used in the current study to establish the turnover rate of hypoxic cells in three different tumor models. The first hypoxic marker, pimonidazole, was administered at variable times before tumor harvest, and the second hypoxic marker, CCI-103F, was injected at a fixed time before harvest. Hypoxic cell turnover was defined as loss of pimonidazole (first marker) relative to CCI-103F (second marker). RESULTS: The half-life of hypoxic cell turnover was 17 h in the murine C38 colon carcinoma line, 23 h and 49 h in the human xenograft lines MEC82 and SCCNij3, respectively. Within 24 h, loss of pimonidazole-stained areas in C38 and MEC82 occurred concurrent with the appearance of pimonidazole positive cell debris in necrotic regions. In C38 and MEC82, most of the hypoxic cells had disappeared after 48 h, whereas in SCCNij3, viable cells that had been labeled with pimonidazole were still observed after 5 days. CONCLUSIONS: The present study demonstrates that the double hypoxia marker assay can be used to study changes in both the proportion of hypoxic tumor cells and their lifespan at the same time. The present study shows that large differences in hypoxic cell turnover rates may exist among tumor lines, with half-lives ranging from 17-49 h.

Animals↗

PubMed2005

Irradiation combined with SU5416: microvascular changes and growth delay in a human xenograft glioblastoma tumor line.

PURPOSE: The combination of irradiation and the antiangiogenic compound SU5416 was tested and compared with irradiation alone in a human glioblastoma tumor line xenografted in nude mice. The aim of this study was to monitor microenvironmental changes and growth delay. METHODS AND MATERIALS: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without SU5416. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after imunohistochemical staining. Tumor growth delay was monitored for up to 200 days after treatment. RESULTS: SU5416, when combined with irradiation, has an additive effect over treatment with irradiation alone. Analysis of the tumor microenvironment showed a decreased vascular density during treatment with SU5416. In tumors regrowing after reaching only a partial remission, vascular characteristics normalized shortly after cessation of SU5416. However, in tumors regrowing after reaching a complete remission, permanent microenvironmental changes and an increase of tumor necrosis with a subsequent slower tumor regrowth was found. CONCLUSIONS: Permanent vascular changes were seen after combined treatment resulting in complete remission. Antiangiogenic treatment with SU5416 when combined with irradiation has an additive effect over treatment with irradiation or antiangiogenic treatment alone.

Angiogenesis Inhibitors↗

PubMed2005

Comparison of different methods of CAIX quantification in relation to hypoxia in three human head and neck tumor lines.

PURPOSE: In head and neck cancer, it has been shown that hypoxic tumors respond poorly to therapy. Methods to identify hypoxic tumors are, therefore, of importance to select patients for oxygenation modifying or other intensified treatments. The aim of this study was to compare tumor cell hypoxia assessed by the hypoxic cell marker pimonidazole (PIMO) with expression of the endogenous hypoxia-related marker carbonic anhydrase IX (CAIX) in three human head and neck tumor lines. MATERIAL AND METHODS: Forty-five tumors of three human head and neck tumor lines, SCCNij3, SCCNij59 and MEC82, xenografted in athymic mice, were used. CAIX was quantified by biodistribution (% injected dose/g tumor) after injecting 3-5 microl 111In-labeled G250 mouse antibody 3 days prior to euthanizing. In a tissue section from the same tumor, fractions of tumor area positive for PIMO, CAIX and Hoechst 33342 (perfusion marker) were assessed after immunohistochemical staining, using a digital image analysis system. RESULTS: SCCNij3 and MEC82 were relatively hypoxic tumor lines with fractions of tumor area positive for pimonidazole of 0.16 and 0.15, respectively. SCCNij59 was a better-oxygenated tumor line with a PIMO-fraction of 0.03. The three tumor lines showed different levels and patterns of CAIX immunohistochemical staining, but only in MEC82 there was a good correlation between PIMO-fraction and CAIX-fraction (r2=0.92, P<0.0001). Correlations between 111In-G250 uptake and CAIX-fraction or PIMO-fraction within tumor lines were weak or absent. CONCLUSIONS: Assessment of CAIX expression depends largely on the techniques and tumor lines used. Furthermore, the immunohistochemical staining pattern of CAIX relative to PIMO differs between human tumor lines of similar anatomical origin. Therefore, the use of CAIX as endogenous marker of tumor hypoxia remains questionable.

Animals↗

PubMed2004

Effects of nicotinamide and carbogen in different murine colon carcinomas: immunohistochemical analysis of vascular architecture and microenvironmental parameters.

PURPOSE: To investigate oxygenation, perfusion, and cell proliferation in two murine colon carcinoma lines with known differences in chemotherapy sensitivity and analyze the effect of nicotinamide and carbogen on these tumor characteristics. METHODS AND MATERIALS: Mice with s.c. transplanted C38 and C26a murine colon tumors were treated with nicotinamide and carbogen and compared with control tumors. Two markers of hypoxia, CCI-103F and pimonidazole, were injected before and after treatment with nicotinamide/carbogen, respectively, allowing each tumor to serve as its own control. Hoechst33342 was used as a perfusion marker and bromodeoxyuridine (BrdUrd) as a proliferation marker. Frozen tumors were cut for multistep immunostaining and computer-controlled microscope scanning for hypoxic fractions (HF), perfused fractions (PF), vascular density, and BrdUrd-labeling index (LI). RESULTS: Microscopic observation of C38 and C26a tumors showed extensive differences in vascular architecture, distribution patterns of hypoxia, and BrdUrd-labeling. Quantitative analysis of C38 and C26a tumors showed a decrease in HF in response to all treatment modalities. For C38 tumors, the average decrease in HF in response to carbogen containing treatments was larger than to nicotinamide alone. In C26a tumors, no difference in average decrease in HF was observed between the treatments. The PF of C38 and C26a did not change in response to treatment. The LI of C38 and C26a decreased upon all treatments, which was statistically significant in the combination treatment of C38. CONCLUSIONS: The mechanism that can simultaneously explain all the observed changes in response to treatment may be the conversion of metabolism from less respiration toward more glycolysis due to increased glucose levels (Crabtree effect), although other mechanisms of actions cannot be excluded.

Animals↗

PubMed2004

Clinical studies of hypoxia modification in radiotherapy.

Hypoxic modification has been the subject of investigations in clinical radiation oncology since the early 60s. To date, this has not yet resulted in a treatment that has been widely accepted. Logistics and technical difficulties limit the routine use of hyperbaric oxygen in radiotherapy. The nitroimidazoles have not gained general acceptance, initially because of their toxicity and later because of doubts about the effectiveness of the newer generation of less toxic drugs. Nevertheless, there is good evidence from these studies that improving clinical outcome by hypoxic modulation is an achievable goal. Newer approaches including combinations of radiotherapy with tirapazamine, erythropoietin, and carbogen and nicotinamide (ARCON) are currently in phase III trial. For these new strategies to be successful, it is important that the proper patient categories are selected. Various methods to assess tumor oxygenation are now becoming available in the clinic. These potential predictive assays must be incorporated and validated in current and future large-scale clinical trials. Modifiers that target other aspects of tumor biology may also have indirect effects on tumor oxygenation. These aspects require further study in preclinical and early clinical settings.

Antineoplastic Agents↗

PubMed2003

Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers.

BACKGROUND AND PURPOSE: Tumor oxygenation is recognized as an important determinant of the outcome of radiotherapy and possibly also of other treatment modalities in a number of tumor types and in particular in squamous cell carcinomas. The hypoxic status of various solid tumors has been related to a poor prognosis due to tumor progression towards a more malignant phenotype, with increased metastatic potential, and an increased resistance to treatment. It has been demonstrated in head and neck cancer that hypoxic radioresistance can be successfully counteracted by hypoxia modifying approaches. The microregional distribution and the level of tumor hypoxia depend on oxygen consumption and temporal and spatial variations in blood supply. It is unclear if severely hypoxic cells can resume clonogenicity when O(2) and nutrients become available again as a result of (treatment related) changes in the tumor microenvironment. Non-terminally differentiated hypoxic cells that are capable of proliferation are important for outcome because of their resistance to radiotherapy and possibly other cytotoxic treatments. Various exogenous and endogenous markers for hypoxia are currently available and can be studied in relation to each other, the tumor architecture and the tumor microenvironment. Use of nitroimidazole markers with immunohistochemical detection allows studying tumor cell hypoxia at the microscopic level. Co-registration with other microenvironmental parameters, such as vascular architecture (vascular density), blood perfusion, tumor cell proliferation and apoptosis, offers the possibility to obtain a comprehensive functional image of tumor patho-physiology and to study the effects of different modalities of cancer treatment. CONCLUSION: A number of functional microregional parameters have emerged that are good candidates for future use as indicators of tumor aggressiveness and treatment response. The key question is whether these parameters can be used as tools for selection of treatment strategies for individual patients. This requires testing of these markers in prospective randomized clinical trials comparing standard treatment against experimental treatments targeting the relevant microregional constituent.

Antigens, Neoplasm↗

PubMed2002

Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer.

Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation treatment. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. This study correlated the exogenous 2-nitroimidazole hypoxia marker 1-[(2-hydroxy-3-piperidinyl)propyl]-2-nitroimidazole hydrochloride (pimonidazole) with the endogenous hypoxia-related marker carbonic anhydrase 9 (CA9) and with vascular parameters using immunohistochemical techniques and a computerized image analysis system. Tumor biopsies were obtained from patients with head and neck carcinomas that were potential candidates for a Phase II trial with accelerated radiotherapy combined with carbogen and nicotinamide (ARCON). If, after completion of the diagnostic workup, the eligibility criteria were met and informed consent was obtained, patients were treated with ARCON. Those patients that were not eligible or refused ARCON were treated with radiotherapy, surgery, or a combined modality. Forty-three biopsies were analyzed, and the results were related with treatment outcome. The distribution patterns of pimonidazole and CA9 were similar, although the CA9 signal was generally observed already at shorter distances from blood vessels. There was a weak but significant correlation between the relative tumor areas positive for pimonidazole binding and areas with CA9 expression. Locoregional tumor control was significantly lower for patients who had hypoxic tumors or tumors with low vascular density. The 2-year control rates were 48 versus 87% for tumors with high and low pimonidazole binding levels (stratified by median, P = 0.01) and 48 and 88% for tumors with low and high vascular density (stratified by median, P = 0.01). These associations disappeared in the subgroup of patients treated with ARCON. There was no relationship between the level of CA9 expression and treatment outcome. It is concluded that pimonidazole binding and vascular density can predict treatment outcome in head and neck cancer and may be useful as selection tools for hypoxia-modifying treatments. Pimonidazole and CA9 demonstrate concordant staining patterns, but the latter is a less specific marker for hypoxia.

Adult↗

PubMed2002

Vascular architecture, hypoxia, and proliferation in first-generation xenografts of human head-and-neck squamous cell carcinomas.

PURPOSE: To quantify the physiologic status of human tumor cells in relation to the tumor vasculature. METHODS AND MATERIALS: Fourteen tumors of 11 first-generation xenograft lines of human head-and-neck squamous cell carcinoma were injected with the hypoxic cell marker pimonidazole, the proliferation marker BrdUrd, and the perfusion marker Hoechst 33342. Consecutive tissue sections were processed with immunohistochemical methods and analyzed with image-analysis techniques. RESULTS: Three different hypoxic patterns were found: patchy, ribbon-like, and mixed. An image-analysis method was developed to quantify these, and an elongation index (length/width) was calculated for hypoxia. The mean elongation indices ranged from 2.0 to 28.3 and showed a good correlation with the visual scoring of hypoxic patterns. Comparative analysis of hypoxic and proliferating cells in zones around the tumor vasculature showed the presence of both hypoxic and proliferating cells in all zones up to 250 microm from the vessels. The largest coexistence of hypoxic and proliferating cells seemed to occur at 50-100 microm from the vessels. CONCLUSIONS: The three hypoxic patterns could be quantified by an elongation index, which is an additional parameter that allows distinction of tumors with similar fractions of hypoxic cells. The analysis of hypoxic and proliferating cells as a function of distance from the tumor vasculature indicates that proliferation does occur also at low oxygen tensions.

Animals↗

PubMed2002

Pharmacology and toxicity of nicotinamide combined with domperidone during fractionated radiotherapy.

BACKGROUND AND PURPOSE: Treatment of head and neck tumors by the ARCON regimen has yielded high local control rates. As a result of this treatment intensification there was some increase in mainly acute toxicity of radiotherapy, but nicotinamide by itself has specific side effects such as nausea and vomiting. Due to these side effects and with the initial dose of 80 mg/kg, 31% of the patients discontinued nicotinamide intake. The aim of the study was to investigate the effect of a dose reduction to 60 mg/kg, and the addition of domperidone on the side effects of nicotinamide and its pharmacokinetic profile. PATIENTS AND METHODS: In 22 patients blood plasma nicotinamide levels were determined after intake of 60 mg/kg nicotinamide. A next group of 87 patients received 60 mg/kg nicotinamide in combination with domperidone. In ten of these patients blood plasma nicotinamide levels were also determined. A full pharmacokinetic profile was constructed over the first 24 h after intake of the first drug dose. Furthermore, daily plasma levels at 1 h after nicotinamide intake was determined in the first and last weeks of radiotherapy. All patients were treated according to the ARCON schedule. RESULTS AND DISCUSSION: The mean maximum plasma nicotinamide concentration was 793 nmol/ml without domperidone and 776 nmol/ml with domperidone. The median time at which the maximum concentration occurred was not significantly different for 60 mg/kg nicotinamide without or with domperidone (0.46 versus 0.54 h). The side effects were drastically reduced if nicotinamide was accompanied by domperidone. The percentage of patients that stopped nicotinamide intake was reduced from 32% without domperidone to 14% with domperidone. No correlation was found between the plasma peak concentrations of nicotinamide and the severity of side effects. CONCLUSION: The currently used dose of 60 mg/kg nicotinamide results in a 30% reduction in peak plasma concentrations compared with 80 mg/kg nicotinamide. If nicotinamide was given in combination with domperidone, 86% of the patients continued the nicotinamide medication until the end of the treatment period.

Adult↗

PubMed2002

ARCON: a novel biology-based approach in radiotherapy.

Two mechanisms of radiotherapy resistance which are of major importance in various tumour types are tumour-cell repopulation and hypoxia. ARCON (accelerated radiotherapy with carbogen and nicotinamide) is a new therapeutic strategy that combines radiation treatment modifications, with the aim of counteracting these resistance mechanisms. To limit clonogenic repopulation during therapy, the overall duration of the radiotherapy is reduced, generally by delivering several fractions per day. This accelerated radiotherapy is combined with inhalation of hyperoxic gas to decrease diffusion-limited hypoxia, and nicotinamide, a vasoactive agent, to decrease perfusion-limited hypoxia. Preclinical studies have been done to test the enhancing effects of these three components of ARCON, individually and in combination, in several experimentally induced tumours and normal tissues. In a mouse mammary carcinoma, the tumour-control rate obtained with ARCON was the same as that with conventional treatment, but with a radiation dose almost 50% lower. Phase 1 and 2 clinical trials have shown the feasibility and tolerability of ARCON, and have produced promising results in terms of tumour control. In particular in cancers of the head and neck and bladder, the local tumour-control rates are higher than in other studies, and phase 3 trials for these tumour types are underway. In conjunction with these trials, hypoxia markers detectable by immunohistochemistry are being tested for their potential use in predictive assays to select patients for ARCON and other hypoxia-modifying therapies.

Animals↗

PubMedDate not supplied

Interleukin-12 has no effect on vascular density, perfusion, hypoxia and proliferation of an implanted human squamous cell carcinoma xenograft tumour despite up-regulation of ICAM-1.

BACKGROUND: Interleukin-12 is an anti-angiogenic and antitumor agent in many transplanted murine tumour models. In a previous clinical study in head and neck squamous cell carcinoma patients treated with rhIL-12 the tumour turned pale, after an initial reddening. The aim of this study was to investigate the effects of rmIL-12 on the vasculature, blood perfusion, hypoxia and proliferation of tumour cells in an implanted human head and neck squamous cell carcinoma xenograft tumour, with a relatively large diameter, in Balb/c nu/nu mice over time. MATERIALS AND METHODS: Established human squamous cell carcinoma xenograft tumours were intratumorally injected for 3 days with either 200 ng rmIL-12 or PBA. Mice were sacrificed at 4 different time points (between 8 hours and 8 days after the last injection), after administration of Pimonidazole, BrdUrd and Hoechst 33342. The tumour sections were quantitatively analysed with a semi-automatic method based on a computerised digital image analysis system, after immunohistochemical staining. RESULTS: Despite a faster and higher up-regulation of anti-mouse ICAM-1 in the IL-12-treated tumours, no significant differences in vascular density, perfusion fraction, hypoxic fraction and BrdUrd labelling index were detected between IL-12-treated tumour and control tumours. CONCLUSION: We suggest that the main reason why the observation made in humans could not be confirmed in this mice study is the combination of a lack of an intact immune system in the Balb/c nu/nu mice and a relatively large tumour with probably a lot of mature vessels.

Animals↗