6-Trifluoromethylpyridoxine: novel (19)F NMR pH indicator for in vivo detection.

pH plays an important role in tumor proliferation, angiogenesis, metabolic control, and the efficacy of cytotoxic therapy, and accurate noninvasive assessment of tumor pH promises to provide insight into developmental processes and prognostic information. In this paper, we report the design, synthesis, and characterization of two novel pH indicators 6-trifluoromethylpyridoxine 8 and α(4),α(5)-di-O-[3'-O-(ß-d-glucopyranosyl)propyl]-6-trifluoromethylpyridoxine 17 and demonstrate 8 as an extracellular (19)F NMR pH probe to assess pH(e) of various tumors in vivo.

Spatial gradients of blood vessels and hematopoietic stem and progenitor cells within the marrow cavities of the human skeleton.

This report evaluates the spatial profile of blood vessel fragments (BVFs) and CD34(+) and CD117(+) hematopoietic stem and progenitor cells (HSPCs) in human cancellous bone. Bone specimens were sectioned, immunostained (anti-CD34 and anti-CD117), and digitally imaged. Immunoreactive cells and vessels were then optically and morphometrically identified and labeled on the corresponding digital image. The distance of each BVF, or CD34(+) or CD117(+) HSPC to the nearest trabecular surface was measured and binned in 50-microm increments. The relative concentration of HSPCs and BVFs within cancellous marrow was observed to diminish with increasing distance in the marrow space. On average, 50% of the CD34(+) HSPC population, 60% of the CD117(+) HSPC population, and 72% of the BVFs were found within 100 microm of the bone surfaces. HSPCs were also found to exist in close proximity to BVFs, which supports the notion of a shared HSPC and vessel spatial niche.

Spatial distribution of blood vessels and CD34+ hematopoietic stem and progenitor cells within the marrow cavities of human cancellous bone.

UNLABELLED: Current bone marrow dosimetry methods inherently assume that the target cells of interest for the assessment of leukemia risk (stochastic effects) or marrow toxicity (deterministic effects) are uniformly localized throughout the marrow cavities of cancellous bone. Previous studies on mouse femur, however, have demonstrated a spatial gradient for the hematopoietic stem and progenitor cells, with higher concentrations near the bone surfaces. The objective of the present study was to directly measure the spatial concentration of these cells, as well as marrow vasculature structures, within images of human disease-free bone marrow. METHODS: Core-biopsy samples of normal bone marrow from the iliac crest were obtained from clinical cases at Shands Hospital at the University of Florida Department of Pathology. The specimens were sectioned and immunohistochemically stained for CD34 (red) and CD31 (brown) antigens. These 2 stains were used simultaneously to differentiate between hematopoietic stem and progenitor cells (CD34(+)/CD31(-)) and vascular endothelium (CD34(+)/CD31(+)). Distances from hematopoietic CD34(+) cells and blood vessels to the nearest bone trabecula surface were measured digitally and then binned in 50-mum increments, with the results then normalized per unit area of marrow tissue. The distances separating hematopoietic CD34(+) cells from vessels were also tallied. RESULTS: Hematopoietic CD34(+) cells were found to exist along a linear spatial gradient with a maximal areal concentration localized within the first 50 mum of the bone surfaces. An exponential spatial concentration gradient was found in the concentration of blood vessel fragments within the images. Distances between hematopoietic CD34(+) cells and blood vessels exhibited a lognormal distribution indicating a shared spatial niche. CONCLUSION: Study results confirm that the spatial gradient of hematopoietic stem and progenitor cells previously measured in mouse femur is also present within human cancellous bone. The dosimetric implication of these results may be significant for those scenarios in which the absorbed dose itself is nonuniformly delivered across the marrow tissues, as would be the case for a low-energy beta- or alpha-particle emitter localized on the bone surfaces.

Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor.

PURPOSE: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. METHODS AND MATERIALS: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by (19)F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. RESULTS: Large tumors (>3.0 cm(3)) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO(2)) than their smaller counterparts (<1.5 cm(3)). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO(2), and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO(2) > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. CONCLUSIONS: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy.

Dynamic response of breast tumor oxygenation to hyperoxic respiratory challenge monitored with three oxygen-sensitive parameters.

The simultaneous measurement of three oxygen-sensitive parameters [arterial hemoglobin oxygen saturation (SaO2), tumor vascular-oxygenated hemoglobin concentration ([HbO2]), and tumor oxygen tension (pO2)] in response to hyperoxic respiratory challenge is demonstrated in rat breast tumors. The effects of two hyperoxic gases [oxygen and carbogen (5% CO2 and 95% O2)] were compared, by use of two groups of Fisher rats with subcutaneous 13762NF breast tumors implanted in pedicles on the foreback. Two different gas-inhalation sequences were compared, i.e., air-carbogen-air-oxygen-air and air-oxygen-air-carbogen-air. The results demonstrate that both of the inhaled, hyperoxic gases significantly improved the tumor oxygen status. All three parameters displayed similar dynamic response to hyperoxic gas interventions, but with different response times: the fastest for arterial SaO2, followed by biphasic changes in tumor vascular [HbO2], and then delayed responses for pO2. Both of the gases induced similar changes in vascular oxygenation and regional tissue pO2 in the rat tumors, and changes in [HbO2] and mean pO2 showed a linear correlation with large standard deviations, which presumably results from global versus local measurements. Indeed, the pO2 data revealed hetergeneous regional response to hyperoxic interventions. Although preliminary near-infrared measurements had been demonstrated previously in this model, the addition of the pO2 optical fiber probes provides a link between the noninvasive relative measurements of vascular phenomena based on endogenous reporter molecules, with the quantitative, albeit, invasive pO2 determinations.