Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis

Rijken, P.F.J.W.; Bernsen, H.J.J.A.; Peters, Jan; Hodgkiss, R.J.; Raleigh, James A.; Kogel, Albert J. van der

doi:10.1016/s0360-3016(00)00686-6

Cited by 109 publications

(93 citation statements)

References 42 publications

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“…This implies a diffusion-limited hypoxia, determined by the spatial distribution of the perfused vessels. The values obtained for the relative vascular area in each tumour (Table 2) are very low compared to the results described in the literature (0.052 -0.2), for human glioma xenografts (Rijken et al, 1995(Rijken et al, , 2000. This result could also be explained by the variation in the angiogenic profile of the different sorts of tumours analysed (Rijken et al, 1995;Koukourakis et al, 2000).…”

Section: Localisation Of Hypoxic Regionscontrasting

confidence: 54%

“…This result could also be explained by the variation in the angiogenic profile of the different sorts of tumours analysed (Rijken et al, 1995;Koukourakis et al, 2000). In C6 rat glioma, chronic hypoxia occurs at a minimal distance of 114 mm from a perfused vessel, a value in the range of those already described in the literature (100 -200 mm) (Vaupel et al, 1989;Rijken et al, 2000). From this distance, pimonidazole binding was found to increase from background level to a maximum at the far end of a hypoxic region ( Figure 3A), resulting in a hypoxia gradient.…”

Section: Localisation Of Hypoxic Regionsmentioning

confidence: 85%

“…A multiple fluorescence staining technique combined with a digital image analysis was used to study quantitatively tumour vascularity, perfusion, hypoxia and lipids in the same section (Rijken et al, 2000). Pimonidazole (1-[(2-hydroxy-3-piperidinyl) propyl]-2-nitroimidazole hydrochloride) was used as a hypoxia marker (Kennedy et al, 1997;Durand and Raleigh, 1998;Varia et al, 1998;Raleigh et al, 1999), Hoechst 33342 was utilised for the detection of perfused vasculature, and anticollagen type IV was used as an anatomical marker of all vessels.…”

Section: Immunohistochemistry and Section Analysismentioning

confidence: 99%

“…Tumour and necrosis areas were measured and the data were classed according to the necrotic fraction, R, defined as the necrotic area divided by the total tumour area. Tumour perfusion, vascularity and oxygenation were analysed using the system described by Rijken et al (1995Rijken et al ( , 2000. Briefly, the fluorescence signals were recorded by a high-resolution intensified solid-state black and white video camera.…”

Section: Immunohistochemistry and Section Analysismentioning

confidence: 99%

“…In randomly selected regions of interest (approximately 10 ROIs per tumours), each including at least one perfused vessel near a hypoxic region adjoining tissue necrosis, distances from perfused vessels to necrotic areas, crossing hypoxic regions, were measured in manually drawn rectangles. In addition, pimonidazole-binding intensity as a function of distances to perfused vessels was measured using a 12-bit image analysis system (Rijken et al, 2000).…”

Section: Immunohistochemistry and Section Analysismentioning

confidence: 99%

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Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection

Zoula¹,

Rijken

Peters

et al. 2003

Br J Cancer

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In C6 rat brain glioma, we have investigated the relation between hypoxia and the presence of lipid droplets in the cytoplasm of viable cells adjacent to necrosis. For this purpose, rats were stereotaxically implanted with C6 cells. Experiments were carried out by the end of the tumour development. A multifluorescence staining protocol combined with digital image analysis was used to quantitatively study the spatial distribution of hypoxic cells (pimonidazole), blood perfusion (Hoechst 33342), total vascular bed (collagen type IV) and lipid droplets (Red Oil) in single frozen sections. All tumours (n ¼ 6) showed necrosis, pimonidazole binding and lipid droplets. Pimonidazole binding occurred at a mean distance of 114 mm from perfused vessels mainly around necrosis. Lipid droplets were principally located in the necrotic tissue. Some smaller droplets were also observed in part of the pimonidazole-binding cells surrounding necrosis. Hence, lipid droplets appeared only in hypoxic cells adjacent to necrosis, at an approximate distance of 181 mm from perfused vessels. In conclusion, our results show that severe hypoxic cells accumulated small lipid droplets. However, a 100% colocalisation of hypoxia and lipid droplets does not exist. Thus, lipid droplets cannot be considered as a surrogate marker of hypoxia, but rather of severe, prenecrotic hypoxia.

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Section: Localisation Of Hypoxic Regionscontrasting

confidence: 54%

Section: Localisation Of Hypoxic Regionsmentioning

confidence: 85%

Section: Immunohistochemistry and Section Analysismentioning

confidence: 99%

Section: Immunohistochemistry and Section Analysismentioning

confidence: 99%

Section: Immunohistochemistry and Section Analysismentioning

confidence: 99%

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Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection

Zoula¹,

Rijken

Peters

et al. 2003

Br J Cancer

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Radiosensitizers and Radioprotective Agents

Bump¹,

Hoffman²,

Foye

2003

Burger's Medicinal Chemistry and Drug Discovery

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Various approaches have been developed for diminishing the effects of radiation on normal tissues or enhancing tumor cell killing by ionizing radiation. An important potential use for these agents is to modify the outcome of radiation therapy. Potential radioprotectors or radiosensitizers are organized in this review according to mechanism of action. Most of the agents studied are believed to act by reacting with DNA radicals that are produced within milliseconds of exposure to ionizing radiation. According to this mechanism, protectors restore a single electron to electron‐deficient radicals, preventing degradation of the structure of DNA, whereas sensitizers, such as molecular oxygen or nitroimidazoles, form adducts with these radicals, resulting in damage fixation. WR2721 (Ethyol) is the best‐characterized chemical radioprotector. Preferential activation of WR2721 in certain normal tissues by removal of a phosphate group provides a rationale for selective protection of these tissues. Cytokines and biological modifiers represent an important emerging class of radioprotectors that may be particularly useful in modifying bone marrow injury. Nitroimidazoles have been the most widely studied chemical radiosensitizers. Although clinical results with nitroimidazoles have not been impressive, the potential for this approach has not been fully explored, given that the doses that can be administered have been limited by drug toxicity and supplemental strategies, such as concurrent depletion of endogenous protectors, have not been explored in the clinic. Modifiers of tumor oxygenation represent an important class of radiosensitizers that are currently generating considerable clinical interest. RSR13, a modifier of the oxygen affinity of hemoglobin, is highlighted as an example of the process of drug development for this type of agent.

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Tumor vascular architecture and function evaluated by non‐invasive susceptibility MRI methods and immunohistochemistry

Robinson

Rijken²,

Howe

et al. 2003

Magnetic Resonance Imaging

129

141

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Purpose:To investigate the physiological origins responsible for the varying blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) responses to carbogen (95% O 2 /5% CO 2 ) breathing observed with different tumor types. Materials and Methods:Susceptibility contrast-enhanced MRI using the exogenous blood pool contrast agent NC100150 to determine blood volume and vessel size, and immunohistochemical-derived morphometric parameters, were determined in GH3 prolactinomas and RIF-1 fibrosarcomas, both grown in mice, which exhibited very different BOLD responses to carbogen.Results: Administration of NC100150 increased the R 2 * and R 2 rates of both tumor types, and indicated a significant four-fold larger blood volume in the GH3 tumor. The ratio ⌬R 2 */⌬R 2 showed that the capillaries in the GH3 were two-fold larger than those in the RIF-1, in agreement with morphometric analysis. Carbogen breathing induced a significant 25% decrease in R 2 * in the GH3 prolactinoma, whereas the response in the RIF-1 fibrosarcoma was negligible. Conclusion:Low blood volume and small vessel size (and hence reduced hematocrit) are two reasons for the lack of R 2 * change in the RIF-1 with carbogen breathing. BOLD MRI is sensitive to erythrocyte-perfused vessels, whereas exogenous contrast agents interrogate the total perfused vascular volume. BOLD MRI, coupled with a carbogen challenge, provides information on functional, hemodynamic tumor vasculature.

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Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis

Cited by 109 publications

References 42 publications

Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection

Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection

Radiosensitizers and Radioprotective Agents

Tumor vascular architecture and function evaluated by non‐invasive susceptibility MRI methods and immunohistochemistry

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