Tumor Arterioles Research Articles

The Influence of Preablation Embolization Particle Size on the Size of the Microwave Ablation Zone in a Porcine Orthotopic Renal Tumor Model

PurposeTo combine arterial embolization with different embolic agents, followed by microwave ablation (MWA) in a porcine renal tumor (RT), to evaluate the ideal setting to produce the largest change in the size of the ablation zones (AZs). Materials and MethodsIn a transgenic porcine kidney, 32 sites were inoculation with 28 orthotopic RT produced. Experimental groups (23 tumors) underwent angiography with intra-arterial embolization using various embolic materials (calibrated particles from 40 to 1,200 μm and ethiodized oil) to achieve vascular stasis of the RT. MWA using a standard protocol (3 minutes at 65 W) was subsequently performed for all tumors. Next, a gross and histologic ex vivo analysis of the AZ was performed. ResultsControl group AZ volume without prior embolization was 5.24 cm3 (SD ± 0.55). AZs after embolization with 40 μm, 100 μm, 300–500 μm, 900–1,200 μm particles were significantly larger than those with MWA alone (mean, 15.39 cm3 [SD ± 4.54]; P = .002; 11.07 cm3 [SD ± 1.39]; P = .001; 8.68 cm3 [SD ± 0.77]; P = .001; and 9.90 cm3 [SD ± 1.62]; P = .002, respectively). Liquid embolic ethiodized oil emulsion did not create a significant increase in the AZ (5.92 cm3 [SD ± 1.43 cm3]; P = .492). ConclusionsPre-MWA arterial embolization in a porcine RT model produced a statistically significant increase in the AZ when compared with MWA alone. Using smaller particle size embolic material with distal embolization at the tumor arterioles (50–150 μm) produced the largest, almost 3-fold increase in AZ volume.

Comparison of Bolus Versus Dual-Syringe Administration Systems on Glass Yttrium-90 Microsphere Deposition in an In Vitro Microvascular Hepatic Tumor Model

PurposeTo utilize an in vitro microvascular hepatic tumor model to compare the deposition characteristics of glass yttrium-90 microspheres using the dual-syringe (DS) and traditional bolus administration methods. Materials and MethodsThe microvascular tumor model represented a 3.5-cm tumor in a 1,400-cm3 liver with a total hepatic flow of 160 mL/min and was dynamically perfused. A microcatheter was placed in a 2-mm artery feeding the tumor model and 2 additional nontarget arteries. Glass microspheres with a diameter of 20–30 μm were administered using 2 methods: (a) DS delivery at a concentration of 50 mg/mL in either a single, continuous 2-mL infusion or two 1-mL infusions and (b) bolus delivery (BD) of 100 mg of microspheres in a single 3-mL infusion. ResultsOverall, the degree of on-target deposition of the microspheres was 85% ± 11%, with no significant differences between the administration methods. Although the distal penetration into the tumor arterioles was approximately 15 mm (from the second microvascular bifurcation of the tumor model) for all the cases, the distal peak particle counts were significantly higher for the DS delivery case (approximately 5 × 105 microspheres achieving distal deposition vs 2 × 105 for the BD case). This resulted in significantly higher deposition uniformity within the tumor model (90% for the DS delivery case vs 80% for the BD case, α = 0.05). ConclusionsThe use of this new in vitro microvascular hepatic tumor model demonstrated that the administration method can affect the deposition of yttrium-90 microspheres within a tumor, with greater distal deposition and more uniform tumor coverage when the microspheres are delivered at consistent concentrations using a DS delivery device. The BD administration method was associated with less favorable deposition characteristics of the microspheres.

NO EFFECT OF HEAD UP TILT ON TUMOR PERFUSION IN A RAT PRE‐CLINICAL MODEL OF PROSTATE CANCER

Previous research has demonstrated an enhanced prostate tumor blood flow and oxygenation associated with the augmented mean arterial pressure during exercise. Further, prostate tumor arterioles lack functional smooth muscle and have a diminished myogenic response. Thus, we tested the hypothesis that with elevations in the heart‐to‐prostate tumor hydrostatic gradient 70° head‐up tilt (HUT) would result in an enhanced perfusion of the prostate tumor. An enhanced tumor perfusion may improve tumor oxygenation and radiation therapy outcomes.MethodsDunning AT‐1 tumor cells (1×104) were injected into the ventral prostate of male Copenhagen rats (n=7) and studies were performed ~ 6 weeks after cell injection. After 5 minutes in each body position, fluorescent microspheres (red and blue/green, ~250,000 spheres per label) were injected via the carotid artery in the level and HUT body positions. Blood flow was determined in the tumor, kidneys and soleus muscle. Vascular conductance was calculated as blood flow divided by mean arterial pressure (MAP). Blood flow and conductance rates were calculated and a two‐tailed paired t‐test was conducted to compare values in the level vs. HUT positions.ResultsAverage tumor weight was 7.1 ± 0.5 g. MAP was not different between level and HUT (p = 0.15). Adequate blood flow distribution, as determined by a <15% difference in flow between the left/right kidney and/or soleus muscle, was achieved in all animals. Tumor blood flow was not different between level and HUT (12.0 ± 1.1 vs. 10.4 ± 0.8 ml/100 g/min, respectively). No difference was observed between body positions in tumor vascular conductance (p>0.05).DiscussionContrary to our hypothesis, we did not see any significant differences in either blood flow or vascular conductance in the tumor with HUT. With HUT, the prostate shows an increase in vascular resistance; thus, the combination of immature and co‐opted host tissue arterioles present in tumors may have resulted in an unchanged perfusion of the tumor with tilt. Specifically, there would be an enhanced vascular resistance of the host‐tissue (prostate) that may counter hydrostatic differences in perfusion pressure. These findings suggest that elevations in the hydrostatic gradient via HUT may not be sufficient to enhance prostate tumor perfusion.Support or Funding InformationAmerican Cancer Society RSG 14‐150‐1‐CCE (BJB)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Radioembolization-induced liver disease: a systematic review.

Radioembolization (RE) is a relatively novel treatment modality for primary and secondary hepatic malignancies. Microspheres embedded with a β-emitting radioisotope are injected into the hepatic artery, resulting in microsphere deposition in the tumor arterioles and normal portal triads. Microsphere deposition in nontumorous parenchyma can result in radiation-induced liver injury, with lethal RE-induced liver disease (REILD) at the outer end of the spectrum. The primary aim of this study was to evaluate RE-related hepatotoxicity and present an overview of the currently applied definitions and clinically relevant characteristics of REILD. A systematic literature search on REILD was performed. Studies after the introduction of the term REILD (2008) were screened for definitions of REILD. Hepatotoxicity and applied definitions of REILD were compared. Liver biochemistry test abnormalities occur in up to 100% of patients after RE, mostly self-limiting. The incidence of symptomatic REILD varied between 0 and 31%, although in most reports, the incidence was 0-8%, with a lethal outcome in 0-5%. With the exception of bilirubin, the presentation of hepatotoxicity and REILD was similar for cirrhotic and noncirrhotic patients. No uniform definition of REILD was established in the current literature. Here, we propose a unifying definition and grading system for REILD. RE-related hepatotoxicity is a common phenomenon; symptomatic REILD, however, is rare. Currently, reporting of REILD is highly variable, precluding reliable comparison between studies, identification of risk factors, and treatment developments.

Properdistatin inhibits angiogenesis and improves vascular function in human melanoma xenografts with low thrombospondin-1 expression.

In this study, the effect of properdistatin, a novel peptide derived from the thrombospondin 1 (TSP-1) domain of properdin, was investigated in three melanoma xenograft models with different TSP-1 expression. The tumors were grown in dorsal window chambers and were treated with 80 mg/kg/day properdistatin or vehicle. Morphological parameters of the tumor vasculature were assessed from high resolution transillumination images. Blood supply time (i.e., the time required for arterial blood to flow from a supplying artery to downstream microvessels) and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Gene and protein expression of TSP-1 were assessed with quantitative PCR and immunohistochemistry, respectively. Properdistatin treatment inhibited angiogenesis in low TSP-1 expressing tumors but did not alter the vasculature in high TSP-1 expressing tumors. In low TSP-1 expressing tumors, properdistatin selectively removed small-diameter capillaries, but did not change the morphology of tumor arterioles or tumor venules. Properdistatin also reduced blood supply times and increased plasma velocities, implying that the treatment reduced the geometric resistance to blood flow and improved vascular function.

Modulation of Blood Flow, Hypoxia, and Vascular Function in Orthotopic Prostate Tumors During Exercise

Previous studies have hypothesized that tumor blood flow may be elevated or reduced during exercise, which could impact the tumor microenvironment. However, to date technical limitations have precluded the measurement of tumor blood flow during exercise. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that during exercise tumors would experience 1) diminished vascular resistance, 2) augmented blood flow, 3) increased numbers of perfused vessels, and 4) decreased tissue hypoxia and, furthermore, that the increased perfusion would be associated with diminished vasoconstriction in prostate tumor arterioles. Dunning R-3327 MatLyLu tumor cells were injected into the ventral prostate of male Copenhagen rats aged 4 to 6 months randomly assigned to tumor-bearing (n = 42) or vehicle control (n = 14) groups. Prostate tumor blood flow, vascular resistance, patent vessel number, and hypoxia were measured in vivo in conscious rats at rest and during treadmill exercise, and vasoconstrictor responsiveness of resistance arterioles was investigated in vitro. During exercise there was a statistically significant increase in tumor blood flow (approximately 200%) and number of patent vessels (rest mean ± standard deviation [SD] = 12.7±1.3; exercise mean ± SD = 14.3±0.6 vessels/field; Student t test two-sided P = .02) and decreased hypoxia compared with measurements made at rest. In tumor arterioles, the maximal constriction elicited by norepinephrine was blunted by approximately 95% vs control prostate vessels. During exercise there is enhanced tumor perfusion and diminished tumor hypoxia due, in part, to a diminished vasoconstriction. The clinical relevance of these findings are that exercise may enhance the delivery of tumor-targeting drugs as well as attenuate the hypoxic microenvironment within a tumor and lead to a less aggressive phenotype.

First-in-human fractal methodology for modeling the hepatic arterial tree and tumor microvasculature for 90Y-microsphere brachytherapy.

248 Background: 90Y-microsphere therapy (radioembolization) is an effective and safe brachytherapy procedure for control of unresectable primary and metastatic hepatic malignancies. To advance this treatment approach, a method is proposed which enables complex modeling of the hepatic arterial route, and the tumor microvascular bed in which the radioactive particles will become permanently embedded. Methods: Prior work from our group included hepatic vessel measurements from patients undergoing 90Y-microsphere therapy including geometry, pressure, velocity and waveforms prior to and during microsphere deposition in real time. A computation particle-fluid dynamics model was built for proximal hepatic arteries of 900 microns, which is the limit of current imaging technology. Fractal methods were programmed in C++ for simulations of both normal liver and tumor arterial trees. Our goal was to produce sufficient generations to achieve daughter arterioles of 50 micron diameter in tumors where microspheres typically lodge in clusters. Results: Normal liver and tumor artery trees were created, with malignant vessels employing a random generator at each node resulting in corkscrew, bifurcation and/or trifurcation daughter vessel pattern. Three key variables were: asymmetry ratio of radii of daughter vessels; power law of the type of flow present in vessels (turbulent or laminar); and area ratio, which is the area between daughters and parent vessel. Simulations of up to 250 generations resulted in successful modeling of 50 micron diameter normal and tumor arterioles. Impedance in each vessel (modulus and phase shift) was tested with a large variety of vessel geometries. Conclusions: Fractal methods were used to develop a software tool that can represent the microvasculature of human liver and different organs, and can account for disease states, such as liver tumors. This is accomplished using corkscrew, bifurcating, trifurcating and randomized structured trees. Predictive modeling may now be possible for radioactive or non-radioactive microspheres exiting from a catheter in the hepatic artery to its final position in a tumor end arteriole, or for systemic therapies.

Multiple Microvascular Alterations in Pancreatic Islets and Neuroendocrine Tumors of a Men1 Mouse Model

Vascular therapeutic targeting requires thorough evaluation of the mechanisms activated in the specific context of each particular tumor type. We highlight structural, molecular, and functional microvascular aberrations contributing to development and maintenance of pancreatic neuroendocrine tumors (NETs), with special reference to multiple endocrine neoplasia 1 (MEN1) syndrome, using a Men1 mouse model. Tissue samples were analyzed by immunofluorescence to detect vessel density and pericyte distribution within the endocrine pancreas; expression of angiogenic factors was assessed by immunohistochemistry and quantitative real-time PCR in isolated islets and adenomas cultured under normoxic or hypoxic conditions. The increased vascular density of pancreatic NETs developed in Men1 mice was paralleled by an early and extensive redistribution of pericytes within endocrine tissue. These morphological alterations are supported by, and in some cases preceded by, fine-tuned variations in expression of several angiogenic regulators and are further potentiated by hypoxia. By combining two novel ex vivo and in vivo single-islet and tumor perfusion techniques, we demonstrated that both vascular reactivity and blood perfusion of tumor arterioles are significantly altered in response to glucose and L-nitro-arginine methyl ester. Our findings unravel multiple potential molecular and physiological targets differentially activated in the endocrine pancreas of Men1 mice and highlight the need for in-depth functional studies to fully understand the contribution of each component to development of pancreatic NETs in MEN1 syndrome.

Vascular endothelial growth factor receptor 2 (VEGFr2) expression and recurrence of hepatocellular carcinoma following liver transplantation: The Cleveland Clinic experience

4594 Background: The optimal treatment for hepatocellular carcinoma (HCC) for advanced cirrhosis is deceased donor liver transplantation (LT). However, tumor reoccurrence represents major limitation of long term survival. It is, therefore, important to recognize markers which portend poor prognosis including VEGFr2 expression. We examined the association between VEGFr2 expression and tumor recurrence, following liver transplantation in MELD era. Methods: Of 361 consecutive patients who underwent LT at the Cleveland Clinic between June 2002 and August 2006, 126 patients were diagnosed with HCC. Immunohistochemical staining for VEGFr2 was performed in HCC and corresponding adjacent cirrhotic liver from 79 patients out of 126 patients. Stains were scored by estimating percent of positive surface area in veins, arteries, and sinusoidal lining cells of tumor and adjacent tissues. Binary staining variables were created based on median values. Kaplan-Meier survival analysis was used to assess the association between VEGFr2 staining and either recurrence-free survival (RFS) or overall survival (OS). Analysis was only done on 79 patients who had VEGFr2 staining. Results: 87% of the study patients were males. The mean age was 57 (range, 35–76). 1-year and 2-year RFS was 94% and 78%, respectively, as compared to 89% and 79% for the OS. Patients’ death secondary to complication of liver transplant was not censored. Vascular invasion was consistently associated with HCC recurrence (p<0.01) and overall mortality (p<0.05). Subjects with VEGFr2 overexpression in tumor arterioles (p<0.01), venules (p<0.05), or sinusoids (p<0.05) had worse overall survival. In the RFS analysis, similar trends were detected for VEGFr2 overexpression in all three HCC vascular tissues. Higher expression of VEGFr2 in the sinusoids of adjacent non-tumorous liver portended poorer recurrence-free survival (p<0.05). Conclusions: Elevated VEGFr2 expression in HCC was correlated with worse outcome. VEGFr2 inhibitors such as sorafenib may play a role in preventing tumor reoccurrence. No significant financial relationships to disclose.

Radioembolization for the treatment of unresectable hepatocellular carcinoma: A clinical review

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world. The majority of patients with HCC present with unresectable disease. These patients have historically had limited treatment options secondary to HCC demonstrating chemoresistance to the currently available systemic therapies. Additionally, normal liver parenchyma has shown intolerance to tumoricidal radiation doses, limiting the use of external beam radiation. Because of these limitations, novel percutaneous liver-directed therapies have emerged. The targeted infusion of radioactive microspheres (radioembolization) represents one such therapy. Radioembolization is a minimally invasive transcatheter therapy through which radioactive microspheres are infused into the hepatic arteries that supply tumor. Once infused, these microspheres traverse the hepatic vascular plexus and selectively implant within the tumor arterioles. Embedded within the arterioles, the 90Y impregnated microspheres emit high energy and low penetrating radiation doses selectively to the tumor. Radioembolization has recently shown promise for the treatment of patients with unresectable HCC. The objective of this review article is to highlight two currently available radioembolic devices (90Y, 188Rh) and provide the reader with a recent review of the literature.

Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ET(A) receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ET(A) receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ET(A) antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ET(A) antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors.

Endothelin-1 is a critical mediator of myogenic tone in tumor arterioles: implications for cancer treatment.

Although derived from the host tissue, the tumor vasculature is under the influence of the tumor microenvironment and needs to adapt to the resistance to blood flow inherent to the dynamics of tumor growth. Such vascular remodeling can offer selective targets to pharmacologically modulate tumor perfusion and thereby improve the efficacy of conventional anticancer treatments. Radiotherapy and chemotherapy can, indeed, take advantage of a better tumor oxygenation and drug delivery, respectively, both partly dependent on the tumor blood supply. Here, we showed that isolated tumor arterioles mounted in a pressure myograph have the ability, contrary to size-matched healthy arterioles, to contract in response to a transluminal pressure increase. This myogenic tone was exquisitely dependent on the endothelin-1 pathway because it was completely abolished by the selective endothelin receptor A (ETA) antagonist BQ123. This selectivity was additionally supported by the large increase in endothelin-1 abundance in tumors and the higher density of the ETA receptors in tumor vessels. We also documented by using laser Doppler microprobes and imaging that administration of the ETA antagonist led to a significant increase in tumor blood flow, whereas the perfusion in control healthy tissue was not altered. Finally, we provided evidence that acute administration of the ETA antagonist could significantly stimulate tumor oxygenation, as determined by electron paramagnetic resonance oximetry, and increase the efficacy of low-dose, clinically relevant fractionated radiotherapy. Thus, blocking the tumor-selective increase in the vascular endothelin-1/ETA pathway led us to unravel an important reserve of vasorelaxation that can be exploited to selectively increase tumor response to radiotherapy.

Effects of the interaction between carbogen and nicotinamide on R3230 Ac tumor blood flow in Fischer 344 rats.

Braun, R. D., Lanzen, J. L., Turnage, J. A., Rosner, G. and Dewhirst, M. W. Effects of the Interaction between Carbogen and Nicotinamide on R3230 Ac Tumor Blood Flow in Fischer 344 Rats. Radiat. Res. 155, 724-733 (2001). The purpose of this study was to determine whether there are interactions between carbogen breathing and various doses of nicotinamide at the level of the tumor arteriole that might contribute to the improvement in tumor blood flow and pO(2) that is often seen with this combination treatment. R3230 adenocarcinomas were implanted and grown to 4-5 mm in dorsal skin flap window chambers in F344 rats. Saline or 65, 200 or 500 mg/kg nicotinamide was injected i.p. while the rat breathed air through a face mask. After 20 min, either the breathing gas was switched to carbogen for 60 min or the animal remained on air. Measured end points included diameter of tumor arterioles, tumor perfusion, mean arterial blood pressure, and heart rate. None of the measured parameters were affected by injection of saline or nicotinamide, except at the highest nicotinamide dose (500 mg/kg). Mean arterial blood pressure showed a median decrease of 25% when 500 mg/kg nicotinamide was given. Diameter of tumor arterioles decreased significantly from 5-15 min after 500 mg/kg nicotinamide was given but was back to baseline by 20 min. Blood flow decreased significantly 5-20 min after administration of 500 mg/kg nicotinamide compared to the baseline prior to injection. Carbogen breathing resulted in a small increase in mean arterial blood pressure in all groups. There was a transient decrease in the diameter of tumor arterioles and blood flow during the first 5 min of carbogen breathing that was statistically significant in several groups. In the group injected with 500 mg/kg nicotinamide, the diameter of tumor arterioles increased by about 10% during the first 25 min of carbogen breathing, and blood flow increased by a median of 75% over the level prior to carbogen breathing up to 40 min after carbogen breathing. The increase in flow in this group was most likely caused by the concomitant arteriolar vasodilation. Thus there was direct evidence for an interaction between carbogen breathing and nicotinamide, but only at the dose of 500 mg/kg nicotinamide. Since this dose yields plasma levels of nicotinamide that are higher than can be tolerated clinically, it is uncertain whether these changes in arteriolar diameter and blood flow would occur in human tumors.

Microvessel diameters of human colon adenocarcinoma during acute treatment with serotonin.

Modulation of tumor blood flow could be of clinical importance, especially when it is combined with radio- or chemotherapy. Serotonin (5-HT), a naturally occurring agent, selectively reduces tumor blood flow and consecutively inhibits the growth of many animal tumors. Therefore, we introduce a new preparation that allows the study of topically applied 5-HT (10(-8) to 10(-2) mol/l) in the microcirculation of a human colon adenocarcinoma. This tumor has been xenotransplanted subcutaneously under the dorsal surface of the ear in athymic nude mice. 5-HT was also tested in the normal skin. The microvascular diameters of large and small arterioles (A1-3) and venules (V1-4) as well as capillaries were measured via closed-circuit videomicroscopy. Normal skin arterioles and venules constricted at higher doses (> 10(-7) mol/l) of 5-HT. In human colon carcinoma, doses of 5-HT higher than 10(-7) mol/l caused constriction of these microvessels; yet, tumor arterioles constricted more than skin arterioles. Thus, 5-HT could selectively reduce blood flow of human colon adenocarcinoma. Based on these findings, we suggest that 5-HT can inhibit growth of human tumors by selectively constricting tumor arterioles.

Reduction in tumor blood flow in skin flap tumor after hydralazine is not due to a vascular steal phenomenon

AbstractThe purpose of this study was to evaluate whether a “vascular steal” mechanism (preferential arteriolar vasodilation in normal vs. tumor tissue concomitant with a reduction in blood pressure) is responsible for tumor blood flow reduction after hydralazine administration. Fischer‐344 rats, fitted with dorsal flap window chambers that allowed visualization of tumor and normal healing subcutaneous tissue vasculature, were the experimental subjects. Intravital microscopy of tumor and normal microvasculature was used to measure microvessel diameters and red cell velocities before and after hydralazine (0.4 mg/kg, i.v.) administration. Hydralazine caused an average drop in mean arterial pressure of 32 mmHg and a concomitant 70% drop in capillary and venous blood flow in central tumor regions in both 9‐ and 14‐day‐old tumors. Intermittent blood flow frequency increased in capillaries and veins from 3% prior to drug to 46% after drug administration. In contrast, capillary and venous flow increased in adjacent normal tissues by 30%. Normal and tumor arterioles showed no significant change in diameter after hydralazine administration. Since the reductions in tumor blood flow were not accompanied by preferential arteriolar dilation in normal arterioles, the hypothesis that a vascular steal phenomenon was responsible for the observed reduction in tumor blood flow in this model system was disproved. A more likely explanation is that the reduction in tumor vessel diameter and concomitant flow reduction are a passive effect related to the relative difference between intravascular pressure and interstitial fluid pressure and/or tissue pressures, the latter of which are known to be increased in tumors. The results suggest that reduction in tumor blood flow might be expected following blood pressure reduction, even when the tumor resides in normal tissue beds that are not actively vasodilated by an antihypertensive agent. © 1994 Wiley‐Liss, Inc.

A Comparison of the Effects of Photodynamic Therapy on Normal and Tumor Blood Vessels in the Rat Microcirculation

The effects of light activation of the tumor photosensitizer dihematoporphyrin ether (DHE) were studied in the microcirculation of the rat cremaster muscle. Arterioles and venules in an implanted chondrosarcoma were studied by in vivo television microscopy and were compared to normal vessels of the same size elsewhere in the preparation and in control preparations. Activation with green light (530-560 nm, 200 mW/cm2, 120 J/cm2) 48 h after intraperitoneal injection of DHE (10 mg/kg body wt) resulted in significant narrowing of diameters of red blood cell columns in tumor arterioles and venules. The response in normal and control arterioles and venules was not significantly different from that seen in the tumor vessels except that the control arterioles did not remain significantly constricted during the treatment period. Treatment resulted in stasis of blood flow in 90% of tumor and normal arterioles at the completion of light activation. In venules, stasis of blood flow was observed in 75% of tumor and 70% of normal vessels. Vasoconstriction was the primary response in arterioles, while thrombosis predominated in venules. Morphologic assessment of light-activated vessels in the cremaster preparation by transmission electron microscopy revealed platelet aggregation with damage to endothelial cells and smooth muscle cells. Perivascular effects observed included interstitial edema and damage to skeletal muscle cells. In the tumor-bearing preparation, no direct cytotoxic effect on the tumor cells was shown. The surrounding vessels exhibited similar vascular stasis, but the lining cells appeared minimally affected. Photoactivation of DHE results in significant changes in the microcirculation which lead to stasis of blood flow. In this model, the response was similar for the normal microvasculature and for the microcirculation of an implanted chondrosarcoma. These effects may account, in part, for the mechanism of action of photodynamic therapy.