Pimonidazole: A Novel Hypoxia Marker for Complementary Study of Tumor Hypoxia and Cell Proliferation in Cervical Carcinoma

Varia, Mahesh A.; Calkins-Adams, Dennise P.; Rinker, Lillian H.; Kennedy, Andrew S.; Novotny, Debra B.; Fowler, Wesley C.; Raleigh, James A.

doi:10.1006/gyno.1998.5163

Cited by 278 publications

(226 citation statements)

References 24 publications

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“…In addition, also CA IX, an endogenous indicator of hypoxia, was used. Microscopy-based point counting, a method used in morphometric tissue analysis (Weibel, 1981) and also in our study, is next to computerised image analysis shown to be an adequate method for quantification of hypoxia in tumours (Varia et al, 1998).…”

Section: Discussionmentioning

confidence: 60%

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

et al. 2004

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This study aimed to evaluate tumour hypoxia by comparing [ 18 F]Fluoromisonidazole uptake measured using positron emission tomography ([ 18 F]FMISO-PET) with immunohistochemical (IHC) staining techniques. Syngeneic rhabdomyosarcoma (R1) tumour pieces were transplanted subcutaneously in the flanks of WAG/Rij rats. Tumours were analysed at volumes between 0.9 and 7.3 cm 3 . Hypoxic volumes were defined using a 3D region of interest on 2 h postinjection [ 18 F]FMISO-PET images, applying different thresholds (1.2 -3.0). Monoclonal antibodies to pimonidazole (PIMO) and carbonic anhydrase IX (CA IX), exogenous and endogenous markers of hypoxia, respectively, were used for IHC staining. Marker-positive fractions were microscopically measured for each tumour, and hypoxic volumes were calculated. A heterogeneous distribution of hypoxia was observed both with histology and

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Section: Discussionmentioning

confidence: 60%

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

et al. 2004

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“…The availability of histological markers of hypoxia has widened the opportunity to study tumours in more remote sites. The binding of pimonidazole adducts is perhaps the most robust and widely accepted marker of cellular hypoxia (Varia et al, 1998;Nordsmark et al, 2001;Raleigh et al, 2001;Kaanders et al, 2002). However, the technique is invasive as it requires an injection of pimonidazole to be scheduled prior to surgical procedures.…”

Section: Discussionmentioning

confidence: 99%

GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON

et al. 2003

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Glucose transporter-1 protein (GLUT1) and carbonic anhydrase IX (CAIX) are regulated by hypoxia inducible factor-1 (HIF-1) and have been studied as putative intrinsic cellular markers for hypoxia. This study directly compares CAIX and GLUT1 with pimonidazole binding in a prospective series of bladder cancer patients and also studies the prognostic significance of the markers, in combination with vascularity and proliferation, in a retrospective series of bladder cancer patients treated in a phase II trial of radical radiotherapy with carbogen and nicotinamide (ARCON). A total of 21 patients with a diagnosis of transitional cell carcinoma of the bladder received 0.5 g m À2 pimonidazole. Serial tumour sections were stained for pimonidazole, GLUT1 and CAIX and compared. Tissue sections obtained from a series of 64 patients previously treated for invasive bladder cancer using ARCON were stained for GLUT1 and CAIX together with Ki-67 and CD31/34. There was a good geographical colocalisation of both intrinsic markers with pimonidazole and a highly significant agreement in individual patients; correlation coefficients were 0.82 (P ¼ 0.0001) for GLUT1 and 0.74 (Po0.0001) for CAIX. In both series of patients, the intrinsic hypoxia markers were highly correlated with each other and a correlation with proliferation was also evident in the retrospective study. In univariate and multivariate analyses, GLUT1 and CAIX were independent predictors for overall and cause specific survival. The hypoxia markers did not predict for local control or metastases-free survival although higher Ki-67 indices showed a trend towards local failure. The data suggest that both hypoxia modification and accelerated treatment may be valid treatment options in bladder cancer.

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“…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%

“…Presently, the use of molecules derived from 2-nitroimidazole, which are selectively reduced in the presence of a low oxygen concentration, has been adapted to nonradioactive immunohistochemical assays for the detection of hypoxic cells. Pimonidazole has now been applied to human tumours (Kennedy et al, 1997;Varia et al, 1998;Raleigh et al, 1999). This marker is sensitive to the oxygen variations: it is metabolized at pO 2 lower than 10 mmHg, only in viable cells (Durand and Raleigh, 1998;Evans et al, 2000).…”

Section: Localisation Of Hypoxic Regionsmentioning

confidence: 99%

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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Pimonidazole: A Novel Hypoxia Marker for Complementary Study of Tumor Hypoxia and Cell Proliferation in Cervical Carcinoma

Cited by 278 publications

References 24 publications

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON

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

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