Immunohistochemical assessment of intrinsic and extrinsic markers of hypoxia in reproductive tissue: differential expression of HIF1α and HIF2α in rat oviduct and endometrium.

Hypoxia is thought to be critical in regulating physiological processes within the female reproductive system, including ovulation, composition of the fluid in the oviductal/uterine lumens and ovarian follicle development. This study examined the localisation of exogenous (pimonidazole) and endogenous [hypoxia inducible factor 1α and 2α (HIF1α, -2α), glucose transporter type 1 (GLUT1) and carbonic anhydrase 9 (CAIX)] hypoxia-related antigens within the oviduct and uterus of the rat reproductive tract. The extent to which each endogenous antigen co-compartmentalised with pimonidazole was also assessed.

Non-invasive in vivo imaging of vessel calibre in orthotopic prostate tumour xenografts.

Susceptibility contrast magnetic resonance imaging (MRI), utilising ultrasmall superparamagnetic iron oxide (USPIO) particles, was evaluated for the quantitation of vessel size index (Rv, μm), a weighted average measure of tumour blood vessel calibre, and fractional tumour blood volume (fBV, %), in orthotopically propagated murine PC3 prostate tumour xenografts. Tumour vascular architecture was assessed in vivo by MRI prior to and 24 hr after treatment with 200 mg/kg of the vascular disrupting agent ZD6126. A Bayesian hierarchical model (BHM) was used to reduce the uncertainty associated with quantitation of Rv and fBV.

Bayesian estimation of changes in transverse relaxation rates.

Although the biasing of R(2)* estimates by assuming magnitude MR data to be normally distributed has been described, the effect on changes in R(2)* (DeltaR(2)*), such as induced by a paramagnetic contrast agent, has not been reported. In this study, two versions of a novel Bayesian maximum a posteriori approach for estimating DeltaR(2)* are described and evaluated: one that assumes normally distributed data and the other, Rice-distributed data. The approach enables the robust, voxelwise determination of the uncertainty in DeltaR(2)* estimates and provides a useful statistical framework for quantifying the probability that a pixel has been significantly enhanced.

Intrinsic susceptibility MR imaging of chemically induced rat mammary tumors: relationship to histologic assessment of hypoxia and fibrosis.

Purpose: To investigate relationships between magnetic resonance (MR) imaging measurements of R2* and carbogen-induced DeltaR2* in vivo with subsequent histologic assessment of grade, hypoxia, fibrosis, and necrosis in a chemically induced rat mammary tumor model.

Materials And Methods: All experiments were performed in accordance with the local ethics review panel, the UK Home Office Animals Scientific Procedures Act of 1986, and the UK Co-ordinating Committee on Cancer Research guidelines. Of 30 rats injected with N-methyl-N-nitrosourea, 17 developed mammary tumors.

Robust estimation of the apparent diffusion coefficient (ADC) in heterogeneous solid tumors.

The least-squares algorithm is known to bias apparent diffusion coefficient (ADC) values estimated from magnitude MR data, although this effect is commonly assumed to be negligible. In this study the effect of this bias on tumor ADC estimates was evaluated in vivo and was shown to introduce a consistent and significant underestimation of ADC, relative to those given by a robust maximum likelihood approach (on average, a 23.4 +/- 12% underestimation).

Vessel size index magnetic resonance imaging to monitor the effect of antivascular treatment in a rodent tumor model.

Purpose: Vascular disrupting agents are anticancer agents that typically produce a cytostatic tumor response. Vessel size index magnetic resonance imaging (MRI) allows for the estimation of the fractional blood volume (fBV) and blood vessel size (Rv). We assessed whether the vessel size index parameters provided imaging biomarkers for detecting early tumor response to a vascular disrupting agent.

Assessment of tumor response to the vascular disrupting agents 5,6-dimethylxanthenone-4-acetic acid or combretastatin-A4-phosphate by intrinsic susceptibility magnetic resonance imaging.

Purpose: To investigate the use of the transverse magnetic resonance imaging (MRI) relaxation rate R(2)(*) (s(-1)) as a biomarker of tumor vascular response to monitor vascular disrupting agent (VDA) therapy.

Methods And Materials: Multigradient echo MRI was used to quantify R(2)(*) in rat GH3 prolactinomas. R(2)(*) is a sensitive index of deoxyhemoglobin in the blood and can therefore be used to give an index of tissue oxygenation.

Rat tumor response to the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid as measured by dynamic contrast-enhanced magnetic resonance imaging, plasma 5-hydroxyindoleacetic acid levels, and tumor necrosis.

The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using K(trans) and the integrated area under the gadolinium time curve (IAUGC) as response biomarkers.

Tumor dose response to the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid, using in vivo magnetic resonance spectroscopy.

Purpose: To use (31)P and (1)H magnetic resonance spectroscopy (MRS) to assess changes in tumor metabolic profile in vivo in response to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with a view to identifying biomarkers associated with tumor dose response.

Experimental Design: In vivo (31)P and (1)H MRS measurements of (a) tumor bioenergetics [beta-nucleoside triphosphate/inorganic phosphate (beta-NTP/Pi)], (b) the membrane-associated phosphodiesters and phosphomonoesters (PDE/PME), (c) choline (mmol/L), and (d) lactate/water ratio were made on murine HT29 colon carcinoma xenografts pretreatment and 6 or 24 hours posttreatment with increasing doses of DMXAA. Following in vivo MRS, the tumors were excised and used for high-resolution (31)P and (1)H MRS of extracts to provide validation of the in vivo MRS data, histologic analysis of necrosis, and high-performance liquid chromatography.