Measurement Of Tumor Blood Flow Research Articles

18F-EF5: A New PET Tracer for Imaging Hypoxia in Head and Neck Cancer

The aim of this study was to evaluate 2-(2-nitro-(1)H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) labeled with (18)F-fluorine to image hypoxia in patients with squamous cell carcinoma of the head and neck (HNSCC). Fifteen patients with HNSCC were studied. Measurement of tumor blood flow was followed by an (18)F-EF5 PET/CT scan. On a separate day, (18)F-FDG PET/CT was performed to determine the metabolically active tumor volume. In 6 patients, dynamic (18)F-EF5 images of the head and neck area were acquired, followed by static images acquired at 1, 2, and 3 h after injection. In the remaining 9 patients, only static images were obtained. (18)F-EF5 uptake in tumors was compared with that in neck muscle, and the (18)F-EF5 findings were correlated with the (18)F-FDG PET/CT studies. A total of 13 primary tumors and 5 lymph node metastases were evaluated for their uptake of (18)F-EF5. The median tumor-to-muscle (18)F-EF5 uptake ratio (T/M) increased over time and was 1.38 (range, 1.1-3.2) 3 h after tracer injection. The median blood flow in tumors was 36.7 mL/100 g/min (range, 23.3-78.6 mL/100 g/min). Voxel-by-voxel analysis of coregistered blood flow and (18)F-EF5 images revealed a distinct pattern, resulting in a T/M of 1.5 at 3 h to be chosen as a cutoff for clinically significant hypoxia. Fourteen of 18 tumors (78%) had subvolumes within the metabolically active tumor volumes with T/M greater than or equal to 1.5. On the basis of these data, the potential of (18)F-EF5 to detect hypoxia in HNSCC is encouraging. Further development of (18)F-EF5 for eventual targeting of antihypoxia therapies is warranted.

Use of H215O-PET and DCE-MRI to Measure Tumor Blood Flow

Positron emission tomography (PET) with H2(15)O and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provide noninvasive measurements of tumor blood flow. Both tools offer the ability to monitor the direct target of antiangiogenic treatment, and their use is increasingly being studied in trials evaluating such drugs. Antiangiogenic therapy offers great potential and, to an increasing extent, benefit for oncological patients in a variety of palliative and curative settings. Because this type of targeted therapy frequently results in consolidation of the tumor mass instead of regression, monitoring treatment response with the standard volumetric approach (Response Evaluation Criteria in Solid Tumors) leads to underestimation of the response rate. Monitoring direct targets of anticancer therapy might be superior to indirect size changes. In addition, measures of tumor blood flow contribute to a better understanding of tumor biology. This review shows that DCE-MRI and H2(15)O-PET provide reliable measures of tumor perfusion, provided that a certain level of standardization is applied. Heterogeneity in scan acquisition and data analysis complicates the interpretation of study results. Also, limitations inherent to both techniques must be considered when interpreting DCE-MRI and H2(15)O-PET results. This review focuses on the technical and physiological aspects of both techniques and aims to provide the essential information necessary to critically evaluate the use of DCE-MRI and H2(15)O-PET in an oncological setting.

Perfusion Imaging of Brain Tumors Using Arterial Spin-Labeling: Correlation with Histopathologic Vascular Density

We investigated the relationship between tumor blood-flow measurement based on perfusion imaging by arterial spin-labeling (ASL-PI) and histopathologic findings in brain tumors. We used ASL-PI to examine 35 patients with brain tumors, including 11 gliomas, 9 meningiomas, 9 schwannomas, 1 diffuse large B-cell lymphoma, 4 hemangioblastomas, and 1 metastatic brain tumor. As an index of tumor perfusion, the relative signal intensity (SI) of each tumor (%Signal intensity) was determined as a percentage of the maximal SI within the tumor per averaged SI within normal cerebral gray matter on ASL-PI. Relative vascular attenuation (%Vessel) was determined as the total microvessel area per the entire tissue area on CD-34-immunostained histopathologic specimens. MIB1 indices of gliomas were also calculated. The differences in %Signal intensity among different histopathologic types and between high- and low-grade gliomas were compared. In addition, the correlations between %Signal intensity and %Vessel or MIB1 index were evaluated in gliomas. Statistically significant differences in %Signal intensity were observed between hemangioblastomas versus gliomas (P < .005), meningiomas (P < .05), and schwannomas (P < .005). Among gliomas, %Signal intensity was significantly higher for high-grade than for low-grade tumors (P < .05). Correlation analyses revealed significant positive correlations between %Signal intensity and %Vessel in 35 patients, including all 6 histopathologic types (rs = 0.782, P < .00005) and in gliomas (rs = 0.773, P < .05). In addition, in gliomas, %Signal intensity and MIB1 index were significantly positively correlated (rs = 0.700, P < .05). ASL-PI may predict histopathologic vascular densities of brain tumors and may be useful in distinguishing between high- and low-grade gliomas and in differentiating hemangioblastomas from other brain tumors.

Error analysis of tumor blood flow measurement using dynamic contrast-enhanced data and model-independent deconvolution analysis

We performed error analysis of tumor blood flow (TBF) measurement using dynamic contrast-enhanced data and model-independent deconvolution analysis, based on computer simulations. For analysis, we generated a time-dependent concentration of the contrast agent in the volume of interest (VOI) from the arterial input function (AIF) consisting of gamma-variate functions using an adiabatic approximation to the tissue homogeneity model under various plasma flow (Fp), mean capillary transit time (Tc), permeability–surface area product (PS) and signal-to-noise ratio (SNR) values. Deconvolution analyses based on truncated singular value decomposition with a fixed threshold value (TSVD-F), with an adaptive threshold value (TSVD-A) and with the threshold value determined by generalized cross validation (TSVD-G) were used to estimate Fp values from the simulated concentration–time curves in the VOI and AIF. First, we investigated the relationship between the optimal threshold value and SNR in TSVD-F, and then derived the equation describing the relationship between the threshold value and SNR for TSVD-A. Second, we investigated the dependences of the estimated Fp values on Tc, PS, the total duration for data acquisition and the shape of AIF. Although TSVD-F with a threshold value of 0.025, TSVD-A with the threshold value determined by the equation derived in this study and TSVD-G could estimate the Fp values in a similar manner, the standard deviation of the estimates was the smallest and largest for TSVD-A and TSVD-G, respectively. PS did not largely affect the estimates, while Tc did in all methods. Increasing the total duration significantly improved the variations in the estimates in all methods. TSVD-G was most sensitive to the shape of AIF, especially when the total duration was short. In conclusion, this study will be useful for understanding the reliability and limitation of model-independent deconvolution analysis when applied to TBF measurement using an extravascular contrast agent.

A Review of Breast Ultrasound

Frequent advances in transducer design, electronics, computers, and signal processing have improved the quality of ultrasound images to the extent that sonography is now a major mode of imaging for the clinical diagnosis of breast cancer. Breast ultrasound is routinely used for differentiating cysts and solid nodules with high specificity. In combination with mammography, ultrasound is used to characterize solid masses as benign or malignant. There is growing interest in using Doppler ultrasound and contrast agents for measuring tumor blood flow and for imaging tumor vascularity. Ease of use and real-time imaging capability make breast ultrasound a method of choice for guiding breast biopsies and other interventional procedures. Breast ultrasound is used in many forms. B-mode is the most common form of imaging for the breast, although compound imaging and harmonic imaging are being increasingly applied to better visualize breast lesions and to reduce image artifacts. These developments, together with the formulation of a standardized lexicon of solid mass features, have improved the diagnostic performance of breast ultrasound. Several approaches that are currently being investigated to further improve performance include: (1) computer-aided-diagnosis; (2) the assessment of tumor vascularity and tumor blood flow with Doppler ultrasound and contrast agents; and (3) tissue elasticity imaging. In the future, ultrasound will play a greater role in differentiating benign from malignant masses and in the diagnosis of breast cancer.

Measurement of Tumor Blood Flow Using Dynamic Contrast-enhanced Magnetic Resonance Imaging and Deconvolution Analysis

To measure tumor blood flow (TBF) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). A DCE-MRI was performed using inversion recovery-preparation fast-field echo sequences. Dynamic data were obtained every 3.2 seconds for 2 minutes, immediately after gadolinium injection. In 14 patients with malignant musculoskeletal tumors, TBF maps were generated pixel-by-pixel by deconvolution analysis. For preclinical studies, muscle blood flow in 5 volunteers and signal intensities of different gadolinium concentrations were measured. There was a good linear relationship between signal intensities and gadolinium concentrations (r = 0.989, P < 0.001, at gadolinium concentrations <or=2 mmol/L). The average value of muscle blood flow in volunteers was 11.1 +/- 2.7 mL.100 mL.min. In 14 patients with musculoskeletal tumors, TBF showed wide variances: the lowest of 9.6 mL.100 mL.min in liposarcoma and the highest of 182.0 mL.100 mL.min in osteosarcoma. After chemotherapy, the TBF values (7.9, 11.0, and 11.7 mL. 100 mL.min) in the good responders were lower than those (26.8, 31.0, and 62.4 mL.100 mL.min) in the poor responders. A functional map of TBF generated by DCE-MRI and deconvolution analysis would be a promising tool for evaluating tumor blood flow in vivo.

Real‐time In Situ Monitoring of Human Prostate Photodynamic Therapy with Diffuse Light

Photodynamic therapy (PDT) requires oxygen to cause cellular and vascular tumor damage. Tissue oxygen concentration, in turn, is influenced by blood flow and blood oxygenation. Real-time clinical measurement of these hemodynamic quantities, however, is rare. This paper reports the development and application of a probe, combining diffuse reflectance spectroscopy (DRS) for measurement of tumor blood oxygenation and diffuse correlation spectroscopy (DCS) for measurement of tumor blood flow. The instrument was adapted for clinical use during interstitial prostate PDT. Three patients with locally recurrent prostate cancer received 2 mg/ kg motexafin lutetium (MLu) 3 h before illumination and a total light dose of 100 J/cm(2) at 150 mW/cm. Prostrate blood oxygen saturation (StO2) decreased only slightly (approximately 3%) after treatment. On the other hand, prostate blood flow and total hemoglobin concentration over the course of PDT decreased by 50% and 15%, respectively, suggesting MLu-mediated PDT has an anti-vascular effect. While it is certainly impossible to draw definite conclusions from measurements of only three patients, the observed differences in tumor blood flow and blood oxygenation responses during PDT can, in principle, be used to choose among tissue oxygen consumption models and therefore emphasize the potential clinical value for simultaneous monitoring of both parameters.

Functional CT for Quantifying Tumor Perfusion in Antiangiogenic Therapy in a Rat Model

To determine the histologic basis of perfusion parameters measured at functional computed tomography (CT) and to examine the relationship between changes in perfusion and changes in histologic parameters after antiangiogenic therapy in a rat model. This study had institutional animal care and use committee approval. Among 20 Fischer rats with implanted FN13762 tumors in the liver, 10 were treated with SU5416, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, and 10 were treated with the diluent only as control rats. Six rats chosen at random from each group underwent functional CT for the measurement of tumor blood flow, blood volume, mean transit time, and permeability-surface area product. Tumor tissue slides corresponding to functional CT sections were examined to measure tumor microvascular density, number of luminal vessels, vascular perimeter, and vascular area. Two-tailed Student t testing was used to determine differences in growth, numbers of metastases to major organs, vascularity, and perfusion between SU5416-treated and control tumors. Pearson correlation coefficients were used to investigate relationships between vascular parameters. Mean tumor volume and number of metastases, respectively, were lower in SU5416-treated rats than in control rats (1580 mm3 +/- 830 [standard deviation] vs 2330 mm3 +/- 960 and 22.4 +/- 11.0 vs 35.2 +/- 17.3); however, these differences were not significant (P = .084 and P = .079). Mean tumor microvascular density was significantly lower in SU5416-treated rats than in control rats (6.4 vessels per field +/- 4.6 vs 17.2 vessels per field +/- 7.5, P < .001); however, vessel perimeter and vessel area, respectively, were significantly larger in treated rats than in control rats (470 microm per field +/- 320 vs 360 microm per field +/- 270, P = .02; and 4010 microm2 per field +/- 2990 vs 2230 microm2 per field +/- 1750, P = .001). Significant correlations were observed between microvascular density and vessel perimeter and area (r = 0.59 and r = 0.25, respectively; P < .01 for both) in SU5416-treated tumors but not control tumors. Blood flow, blood volume, and permeability-surface area product at functional CT were significantly higher in SU5416-treated tumors than in control tumors (P < .001 for all). These results validate the idea that functional CT can help quantify the perfusion function of mature vessels but not changes in microvessel density in antiangiogenic therapy.

Response

Response

Time course of apoptotic tumor response using 99mTc-annexin V following a single dose of chemotherapy: comparison with immunohistological findings in an experimental animal model

Background and purpose: Annexin V (AV), a human protein with a high affinity for membrane-bound phospholipid (phosphatidylserine, PS), has been labeled with 99mTc and shown to be useful for detecting apoptosis in vivo. We assessed the potential of 99mTc-AV for detecting apoptotic tumor response and examined the change of radioactivity to chemotherapy in an experimental model. Methods: HYNIC-annexin V was labeled with 99mTc ( 99mTc-AV). Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle. Eleven days after tumor inoculation, rats were randomized to receive a single dose of cyclophosphamide (CP; 150 mg/kg, ip) or to serve as control. 99mTc-AV was injected 4, 12 and 20 h following the chemotherapy. Radioactivity in tissues was determined 6 h after injection of 99mTc-AV by means of ex vivo tissue counting. TUNEL and caspase-3 staining was performed to detect apoptosis in the tumor. We measured tumor blood flow by 14C-iodoantipyrine (IAP) on both treated and control rats ( n=4, respectively). Results: Cyclophosphamide treatment significantly increased the tumor uptake of 99mTc-AV at 20 h but not at earlier phases, coinciding with an increased number of immunohistological positive cells. There was no significant change in tumor blood flow by a cyclophosphamide. Conclusions: In vivo detection of apoptosis with 99mTc-Annexin V can be used as a non-invasive means to assess tumor response to chemotherapy without the influence of blood flow. Effective detection required approximately 20 h, not 4 h, for the best timing of annexin V imaging after the start of chemotherapy in a clinical setting.

High-resolution assessment of blood flow in murine RIF-1 tumors by monitoring uptake of H(2)(17)O with proton T(1rho)-weighted imaging.

Perfusion parameters, such as blood flow, are critical properties of tumors related to angiogenesis, drug delivery, radiosensitivity, bioenergetic status, and steady state levels of metabolites, such as lactate, that have been proposed as indices of tumor response to therapy. The existing MR methods for measuring tumor blood flow (TBF) have limitations related to sensitivity, spatial resolution, or dependence on other physiological properties such as vascular permeability. To address many of these difficulties, this study introduces the use of an (17)O-enriched tracer in conjunction with high-resolution, indirect MRI to measure TBF. To demonstrate the advantages of this technique, relative TBF was measured in subcutaneous RIF-1 tumors in C3H mice by monitoring the uptake of H(2) (17)O with a resolution of 0.16 x 0.31 x 3 mm in 13 sec. At this resolution, tumor heterogeneity with respect to blood flow is clearly visible. Measurement of the tracer arterial input function, which is necessary for determination of absolute blood flow, may be facilitated with improved temporal resolution.

Measurement of tumor blood flow using colored dye extraction microspheres in two rat tumor models

A technique that can measure tumor blood flow easily, accurately and economically is required to study tumor angiogenesis and angiogenesis inhibition. Using dye extraction colored microspheres, we measured tumor blood flow in Sato lung carcinoma (SLC) and ascites hepatoma LY80 in rats. Colored microspheres were infused into tumor-bearing rats via a catheter in the left ventricle. After removal of the tumor and the liver, the tissue samples were dissolved, and the microspheres were isolated. Dye was extracted, and the dye concentration was quantified by spectrophotometry. The dye concentration per gram of tumor was compared with that per gram of liver as follows (AU = absorbency units): [AU per gram of tumor] / [AU per gram of liver] X 100 = (%). Tumor blood flow corrected for wet weight was calculated as follows: [blood flow to tumor] = [AU per gram of tumor] X [reference withdrawal rates / [AU per gram of reference blood]. Tumor blood flow rate was divided by tumor weight to yield ml.min. -1 g -1 . The tumors were also examined histologically, and casts of the tumor vasculature were prepared with silicone rubber. Blood flow 2 weeks after transplantation was equivalent to 1/10 and 1/2 at 1 week in SLC and LY80 tumors, respectively (SLC, P=0.009, n=10; LY80, P=0.05, n=10). These decreases in tumor blood flow were associated with underlying pathological and vascular change. Blood flow in LY80 tumors negatively correlated with tumor volume (P=0.009, n=10). We concluded that the colored microsphere method, initially developed to measure organ blood flow, is also useful for estimating tumor blood flow in rats.

Noninvasive estimation of the aorta input function for measurement of tumor blood flow with.

Quantitative measurement of tumor blood flow with [15O]water can be used to evaluate the effects of tumor treatment over time. Since quantitative flow measurements require an input function, we developed the profile fitting method (PFM) to measure the input function from positron emission tomography images of the aorta. First, a [11C]CO scan was acquired and the aorta region was analyzed. The aorta diameter was determined by fitting the image data with a model that includes scanner resolution, the measured venous blood radioactivity concentration, and the spillover of counts from the background. The diameter was used in subsequent fitting of [15O]water dynamic images to estimate the aorta and background radioactivity concentrations. Phantom experiments were performed to test the model. Image quantification biases (up to 15%) were found for small objects, particularly for those in a large elliptical phantom. However, the bias in the PFM concentration estimates was much smaller (2%-6%). A simulation study showed that PFM had less bias and/or variability in flow parameter estimates than an ROI method. PFM was applied to human [11C]CO and [15O]water dynamic studies with left ventricle input functions used as the gold standard. PFM parameter estimates had higher variability than found in the simulation but with minimal bias. These studies suggest that PFM is a promising technique for the noninvasive measurement of the aorta [15O]water input function.

Measurement of tumor blood flow using colored dye extraction microspheres in two rat tumor models.

A technique that can measure tumor blood flow easily, accurately and economically is required to study tumor angiogenesis and angiogenesis inhibition. Using dye extraction colored microspheres, we measured tumor blood flow in Sato lung carcinoma (SLC) and ascites hepatoma LY80 in rats. Colored microspheres were infused into tumor-bearing rats via a catheter in the left ventricle. After removal of the tumor and the liver, the tissue samples were dissolved, and the microspheres were isolated. Dye was extracted, and the dye concentration was quantified by spectrophotometry. The dye concentration per gram of tumor was compared with that per gram of liver as follows (AU = absorbency units): [AU per gram of tumor] / [AU per gram of liver] X 100 = (%). Tumor blood flow corrected for wet weight was calculated as follows: [blood flow to tumor] = [AU per gram of tumor] X [reference withdrawal rate] / [AU per gram of reference blood]. Tumor blood flow rate was divided by tumor weight to yield ml. min-1g-1. The tumors were also examined histologically, and casts of the tumor vasculature were prepared with silicone rubber. Blood flow 2 weeks after transplantation was equivalent to 1/10 and 1/2 at 1 week in SLC and LY80 tumors, respectively (SLC, P=0.009, n=10; LY80, P=0.05, n=10). These decreases in tumor blood flow were associated with underlying pathological and vascular change. Blood flow in LY80 tumors negatively correlated with tumor volume (P=0.009, n=10). We concluded that the colored microsphere method, initially developed to measure organ blood flow, is also useful for estimating tumor blood flow in rats.

Measuring tumor blood flow with H 215O: practical considerations

The ability to measure blood flow to tumors non-invasively may be of importance in monitoring tumor therapies, assessing drug delivery, and understanding tumor physiology. Of all the radiotracer methods that have been proposed to measure tumor blood flow, the method based on labeled water—H 2 15O—may be the most applicable to tumors. It is highly diffusible, does not participate significantly in metabolic processes during the short times involved in the study, and its uptake and clearance can be easily modeled. We present here an analysis of the bolus injection water methodology and how it might best be used to monitor tumor blood flow. Several different formulations of the basic methodology, based on previous applications in the heart and brain, are discussed. Potential problems of adapting these previous methodologies to tumor blood flow are presented.

Tumor blood flow measurements using coincidence counting on patients treated with neutrons

Purpose : The purpose of this work was to measure blood flow in tumors using a coincide counting technique on patients undergoing treatment with neutrons. Methods and Materials : The half-time, T w, for the washout of 15O from neutron-activated tumors was measured with two 10 cm NaI(Tl) crystals coupled to a PC-based coincidence counting system. Blood flow measurements were made in 33 patients, 19 of whom had cancers of the head and neck regions, 6 had breast cancer, 5 had sarcomas, and 3 patients had mesotheliomas. Results : Blood flow as indicated by T w of mobile 15O formed by neutron activation could be readily determined in tumors of patients undergoing neutron radiotherapy. The general reduction in the value for T w was noted towards the end of treatment and did not seem to be dependent on the initial tumor volume. There was a tendency for larger lesions to be associated with longer half-times of 15O washout. Conclusion : It appears possible to obtain a reasonable estimate of tumor blood flow using a simple coincidence counting technique. In view of the large variation in blood flow between tumors, it did not appear to be possible to identify potentially hypoxic tumors that would respond to neutron therapy.

The effects of successive high-energy shock-wave tumor administration on tumor blood flow

The effects of repeated high-energy shock wave (HESW) tumor administration on tumor blood flow (TBF) were studied in NU-1 human kidney cancer xenografts. Deuteriated water was used as a magnetic resonance spectroscopic detectable tracer for measuring tumor blood flow. Tumors were exposed twice to 800 electromagnetically generated HESW, with a 24-h interval or sham exposed. No changes in TBF occurred after sham exposure to HESW. TBF levels 2 h after the first and second HESW application were, respectively, 46% and 37% lower than the mean preexposure TBF value and returned to normal levels within 16 h. There was statistically no difference found between the effects on tumor blood flow after the first and second HESW exposure. These observations are in agreement with earlier studies and provide a rationale to shorten the time interval between HESW monotreatments to 2 to 3 h.

Tumor Blood Flow Measured Using Dynamic Computed Tomography

A method for measuring the tumor blood flow (TBF) by means of dynamic computed tomography (DCT) was devised and investigated. Twenty-seven patients with superficial tumors underwent measurement of TBF by the new DCT method. For all of the 27 patients, the thermal clearance method was employed to measure the relative tumor blood flow (RTBF). For 16 patients, TBF was measured by oxygen-15-gas positron-emission tomography (PET). The TBF values measured by DCT were compared with the RTBF by the thermal clearance method and the TBF by PET. The results demonstrated a linear relationship. The newly devised DCT method yields reliable data in measuring TBF.

Effects of modulation of basic fibroblast growth factor on tumor growth in vivo.

Recombinant human basic fibroblast growth factor (rHu-bFGF) is known to stimulate proliferation in some tumor cells and to modulate tumor vascularization. The purpose of this study was to examine the possible role of this agent in the development of tumors. The study was designed to determine the effects of modulating bFGF activity in vivo in tumor models from cell lines with different responses to bFGF and with different content and receptor levels of bFGF. Two tumor cell lines (human DLD-2 colon carcinoma and rat C6 glioma) were characterized for bFGF content and bFGF receptor levels by Western blot analysis in cultured cells and by studies of [125I]rHu-bFGF binding to sections from xenografts grown in nude mice. Tumor cell proliferation was monitored after treatment with rHu-bFGF or the DG2 or DE6 IgG monoclonal antibody to rHu-bFGF in culture and in vivo. C6 cells exhibited 7800 high-affinity receptors for rHu-bFGF per cell (dissociation constant [Kd] = 46 pM), while DLD-2 cells lacked high-affinity receptors. rHu-bFGF stimulated [3H]thymidine uptake by C6 cells, but the addition of DG2 IgG prevented this stimulation; rHu-bFGF had no effect on [3H]thymidine incorporation by DLD-2 cells. C6 cells had higher levels of immunoreactive bFGF than did DLD-2 cells. The xenografts from both cell lines exhibited high-affinity [125I]rHu-bFGF binding that was concentrated on vascular-like structures. rHu-bFGF at a dosage of 0.25 mg/kg given intraperitoneally daily for 18 days caused a twofold increase in DLD-2 tumor weight but had little effect on the growth of C6 xenografts. In contrast, daily intravenous injections of DG2 IgG given to mice had no effect on DLD-2 tumor growth but reduced growth of C6 tumors by approximately 30%--a statistically significant difference. The addition of exogenous rHu-bFGF or of a neutralizing antibody resulted in significant alterations in tumor growth in vivo, which were specific for tumor type and bFGF characteristics. While some of these effects may be mediated by the bFGF-responsive endothelial cells of the tumor vasculature (DLD-2 colon carcinoma), others may result from inhibition of bFGF-dependent tumor cell proliferation (C6 glioma). Studies that measure tumor blood flow are necessary to confirm that these effects are mediated by changes in tumor vasculature.

Measurement of tumor blood flow by deuterium NMR and the effects of modifiers.

Tumor metabolism is directly coupled to tumor blood flow (TBF) and both metabolism and blood flow may be determinants of tumor response to treatment. Since NMR has been used extensively to monitor tumor metabolism noninvasively, development of NMR-based methods for TBF measurement was motivated by the desire to examine the roles tumor metabolism and blood flow may play as determinants of therapeutic response. The concept of using deuterated water as an NMR-detectable, flow-limited tracer for the measurement of tissue blood flow (or capillary perfusion) was introduced in 1987 by Ackerman and coworkers (Proc. Natl., Acad. Sci., USA 84, 4099-4102 (1987)). Since that time, methods have been devised using both spectroscopic and imaging detection for TBF measurement based on either clearance or uptake of deuterated water. In general, the clearance methods are more straightforward to implement, while the uptake methods are less invasive to the tumor. When used with appropriate caution, both approaches yield reliable results. To date, these methods have been applied in a relatively limited number of animal tumors. However, their use is increasing and some of these methods ultimately should be applicable in human tumors.