Heterogeneous Oxygenation of Rectal Carcinomas in Humans: A Critical Parameter for Preoperative Irradiation?

Wendling, P; Manz, R; Thews, G.; Vaupel, Peter

doi:10.1007/978-1-4684-4895-5_28

Cited by 63 publications

(22 citation statements)

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“…Little is known about the oxygenation of rectal tumours; however, it is likely that hypoxia plays a significant part in determining outcome (Haustermans et al, 2000;Wendling et al, 1984). Furthermore, determination of the level of hypoxia might be important for selecting appropriate preoperative radiotherapy or chemoradiotherapy regimes or determining which patients are more likely to develop distant metastases and therefore require systemic therapy.…”

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confidence: 99%

Glucose transporter-1 (GLUT-1): a potential marker of prognosis in rectal carcinoma?

et al. 2003

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The aim of the study is to evaluate the pattern and level of expression of glucose transporter-1 (GLUT-1) in rectal carcinoma in relation to outcome as a potential surrogate marker of tumour hypoxia. Formalin-fixed tumour sections from 43 patients with rectal carcinoma, who had undergone radical resection with curative intent, were immunohistochemically stained for GLUT-1. A mean of three sections per tumour (range 1 -12) were examined. Each section was semiquantitatively scored; 0, no staining; 1, o10%; 2, 10 -50%; 3, 450% and a score given for the whole section, the superficial (luminal) and deep (mural) part of the tumour. Staining was seen in 70% of tumours. Increased staining was noted adjacent to necrosis and ulceration. A diffuse and patchy pattern of staining, with and without colocalisation to necrosis was seen. Patients with high GLUT-1-expressing tumours (score 3 vs 0 -2) had a significantly poorer overall survival (P ¼ 0.041), which was associated with poorer metastasis-free survival with no difference in local control. No significant correlation was seen with other prognostic factors. There was a strong correlation between the score for the superficial and deep parts of the tumour (r ¼ 0.81), but a significant relationship with outcome was only found in the deep part (P ¼ 0.003 vs P ¼ 0.46). In conclusion, increased GLUT-1 expression in rectal tumours was an adverse prognostic factor and is worth further evaluation as a predictive marker of response to therapy.

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confidence: 99%

Glucose transporter-1 (GLUT-1): a potential marker of prognosis in rectal carcinoma?

et al. 2003

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“…Whether similar events occur in vivo is unknown. Hypoxic cells have been demonstrated in tumours (Powers & Tolmach, 1963;Wendling et al, 1985), as well as the phenomenon of reoxygenation (Rockwell & Moulder, 1985;van Putten & Kallman, 1968). In vivo systems are influenced by many factors, of which hypoxia is just one .…”

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confidence: 99%

“…1981;Martin & McNally, 1980, Smith et al, 1980. Hypoxic regions have also been demonstrated in poorly oxygenated human tumours (Wendling et al, 1985). While We have found a set of proteins, the oxygen regulated proteins (ORPs), whose synthesis is greatly enhanced by hypoxia (Heacock & Sutherland, 1986;Sutherland et al, 1986; al., 1985).…”

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Changes in growth characteristics and macromolecular synthesis on recovery from severe hypoxia

Wilson

Keng²,

Sutherland³

1990

Br J Cancer

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Summary Chinese hamster ovary cells subjected to severe hypoxia stop growing. When oxygen was reintroduced growth resumed, but at a slower rate. The longer the hypoxic stress, the slower the recovery growth rate. Six hours of hypoxia caused very little decrease in growtb rate while a 24 h period almost halved the rate.Short hypoxic periods resulted in almost no growth lag, while longer periods caused significant lag. Clonogenic survival was 60% after 12 h of hypoxia and rose slowly during recovery, reaching control levels after 60 h. Following 24 h of hypoxia, survival remained around 60% throughout recovery. The cell cycle distribution after hypoxia was similar to that of aerobic cultures. After 4-6 h of recovery, a subpopulation of cells entered S phase, and reached G2 by 12 h. During this time few G2-M cells divided. With longer recovery, cells much larger than aerobic cells emerged, containing greater than 4C DNA content and enhanced amounts of RNA. When these cells were isolated, they exhibited slightly slower growth kinetics, greatly lengthened lag time and decreased survival when compared to aerobic cells or the smaller cells. Most of the extra DNA and RNA was lost within one cell cycle.We have found (Wilson et al., 1986) (Koch et al., 1973;Tannock, 1972) and to certain drugs (Born & Eichholtz-Wirth,. 1981;Martin & McNally, 1980, Smith et al., 1980. Hypoxic regions have also been demonstrated in poorly oxygenated human tumours (Wendling et al., 1985). While We have found a set of proteins, the oxygen regulated proteins (ORPs), whose synthesis is greatly enhanced by hypoxia (Heacock & Sutherland, 1986;Sutherland et al., 1986; al., 1985). Briefly, live cells were spun down and resuspended in complete medium to a concentration of 106 cells ml-'. The cells were then kept at 4°C for up to 4 h before staining and flow cytometry. To stain the cells, they were first permeablised by mixing 0.2 ml of the cell suspension with 0.2 ml of a solution containing 0.1 5N NaCl, 0.08N HCI and 0.1% Triton X-100. After one minute, 0.9 ml of the AO stain (121tgml-' AO, 0.15N NaCI, 0.125M Na2 HPO4, 0.037M citric acid, pH 6.0) was added. The sample was then filtered to remove clumps and placed in the flow cytometer. The excitation wavelength was 488 nm. Green fluorescence (IGFL, DNA content) was collected through a 530nm long-pass filter and red fluorescence (IRFL, RNA content) through a 640nm long-pass filter after the fluorescence signals were separated by a 560nm dichroic filter. Forward angle light scatter (FALS), an indicator of cell size, was also measured. Twenty thousand cells were collected for each histogram. Centrifugal elutriationCells were separated into populations enriched in different phases of the cell cycle using centrifugal elutriation. Populations of cells larger than that of normal G2-M phase cells were also obtained using this method. The protocol of Keng et al. (1980) was used. Briefly, 0.5-1 x 10' trypsinised CHO cells were loaded into the separation chamber at a flow rate of 35 ml min-' and rotor spe...

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“…As the tumour mass increases, passive diffusion is no longer adequate to supply metabolic demands (Vaupel et al, 1989). Tumours therefore induce their own microcirculation (angiogenesis) but despite this, areas with low levels of oxygen and essential nutrients persist (Gullino et al, 1967;Wendling et al, 1984). Glucose levels in normal tissues are approximately 5 mM, whereas values for tumours are usually between 0 to 2 mM (Gullino et al, 1967).…”

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Aminolaevulinic acid-induced photodynamic therapy: cellular responses to glucose starvation

et al. 2002

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Photodynamic therapy is a cancer treatment based on the interaction of light, oxygen and a photosensitiser. Protoporphyrin. IX is an endogenous photosensitiser derived from the pro-drug aminolaevulinic acid. Tumours contain areas of hypoxia and hypoglycaemia. Tumour cells adapt to these conditions by stress protein induction which may induce resistance to cancer therapies. The effect of chronic hypoglycaemia on sensitivity to aminolaevulinic acid-induced photodynamic therapy in vitro was studied in MCF-7, human breast cancer cells. Following chronic exposure to 0, 1 or 25 mM, glucose, cells were treated with aminolaevulinic acid and the generation of intracellular protoporphyrin. IX measured by spectrofluorimetry. Aminolaevulinic acid-induced photodynamic therapy sensitivity was compared between cells following chronic exposure to 0, 1 or 25 mM glucose. Percentage cell survival was determined by clonogenic assay. Cells cultured in low glucose generated higher levels of protoporphyrin IX compared to standard glucose medium (0 mM glucose: 0.88610 75 ng cell 71 , 1 mM: 0.86610 75 ng cell 71 , 25 mM: 0.605610 75 ng cell 71 , P50.05). However, photodynamic therapy sensitivity was reduced in glucose deprived cells (0 mM glucose: 61% survival, 1 mM: 80.5% and 25 mM: 39.6%, P50.05). Chronic exposure to low glucose induces photodynamic therapy resistance despite increased intracellular concentrations of protoporphyrin IX and may reflect cellular adaptation to chronic glucose deprivation.

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Heterogeneous Oxygenation of Rectal Carcinomas in Humans: A Critical Parameter for Preoperative Irradiation?

Cited by 63 publications

References 6 publications

Glucose transporter-1 (GLUT-1): a potential marker of prognosis in rectal carcinoma?

Glucose transporter-1 (GLUT-1): a potential marker of prognosis in rectal carcinoma?

Changes in growth characteristics and macromolecular synthesis on recovery from severe hypoxia

Aminolaevulinic acid-induced photodynamic therapy: cellular responses to glucose starvation

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