Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotinamide, an agent previously reported to reduce hypoxia and increase the irradiation response of experimental tumors, has been evaluated for its effect on the occurrence of acute hypoxia in the murine squamous cell tumor SCCVII. Treatment of C3H mice bearing 500-750-mg subcutaneous tumors with nicotinamide (1.0 mg/g intraperitoneally) 1 hour prior to irradiation resulted in an enhancement ratio of 1.3 (+/- 0.1). We assessed the effect of nicotinamide on the response of acutely hypoxic cells in vivo using a recently developed fluorescence-activated-cell sorting technique. This technique employs the in vivo pharmacokinetic and DNA binding properties of the bisbenzamide stain Hoechst 33342. The results clearly show that nicotinamide, at the doses used, reduces the amount of acute hypoxia in these SCCVII tumors. We confirmed these findings using a histological technique that facilitates the assessment of functional tumor vasculature at two instances in time. This method shows that nicotinamide reduces the number of vessels opening and closing over a 20-minute period from 10.3% to 2.0%. The identification of a compound that can modify the dynamic fluctuations in microregional oxygen delivery in tumors could have important implications for radiation therapy.
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PMID:Effect of nicotinamide on the microregional heterogeneity of oxygen delivery within a murine tumor. 213 79

The interaction among nicotinamide, radiation, and heat was studied in vivo using a C3H mouse mammary carcinoma grown in the feet of CDF1 mice. Response following local tumor treatment was assessed by tumor control and regrowth delay. Nicotinamide (1000 mg/kg i.p.) produced maximal radiosensitization when injected 30 min to 2 h before irradiation [enhancement ratios (ERs), 1.2-1.5]. Radiation damage was also increased by heating tumors (43.5 degrees C for 60 min) 4 h after irradiation (ERs = 1.6-2.6). This combined radiation and heat treatment was enhanced by nicotinamide but the effect depended on the assay procedure, such that although a significant increase was observed with the tumor control assay, only a slight increase was seen using regrowth delay as the end point. The development of moist desquamation in normal feet was used to estimate skin damage after irradiation. Nicotinamide and heat both resulted in a small yet significant increase in skin damage (ERs less than 1.2 and 1.1, respectively). A combined treatment resulted in a greater ER of 1.7, but when compared to the tumor response it still gave a therapeutic gain. A histological fluorescent staining technique was used to assess functional tumor vasculature at two periods in time separated by 20 min. Under normal conditions 7.7% of the vessels in this tumor were functional at one time but not the other. This value was reduced to 2.8% after nicotinamide administration. Since these fluctuations in blood flow can result in acute hypoxia we conclude that while heat eliminates chronically hypoxic tumor cells, nicotinamide probably removes the presence of acute hypoxia.
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PMID:Combination of nicotinamide and hyperthermia to eliminate radioresistant chronically and acutely hypoxic tumor cells. 214 77

Hypericin, a polycyclic quinone obtained from plants of the Hypericum genus, exhibits strong photodynamic antitumor effects. In the present study, PDT efficacy of hypericin under different conditions was compared in a P388 mouse tumor model. Plasma and tumor drug measurements and assessment of vascular damage by fluorescein dye exclusion were performed to determine the relative contributions of vascular effects and direct tumor cytotoxicity. Furthermore, the influence of modifying tumor oxygenation on PDT effect was also evaluated. Study of PDT efficacy and tissue distribution revealed that PDT efficacy was more dependent on plasma concentration than tumor drug level. Fluorescein dye exclusion indicated the complete microvascular occlusion in the tumor and surrounding skin immediately after effective PDT treatments, while only a limited vascular occulation was observed after non-effective PDT treatment. It was found that neither tumor hypoxia induced by hydralazine nor increasing tumor oxygenation achieved by nicotinamide could significantly affect the effectiveness of various PDT protocols. These results suggest that tumor vasculature damage might be the primary mechanism of hypericin-mediated PDT effect. The existence of this potent secondary vascular effect is likely to account for the inability of tumor oxygenation modifiers to affect tumor response after PDT with hypericin.
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PMID:Photodynamic therapy with hypericin in a mouse P388 tumor model: vascular effects determine the efficacy. 1125 Nov 68

Assessment of the oxygenation status of brain tumors has been studied increasingly with imaging techniques in light of recent advances in oncology. Tumor oxygen tension is a critical factor influencing the effectiveness of radiation and chemotherapy and malignant progression. Hypoxic tumors are resistant to treatment, and prognostic value of tumor oxygen status is shown in head and neck tumors. Strategies increasing the tumor oxygenation are being investigated to overcome the compromising [figure: see text] effect of hypoxia on tumor treatment. Administration of nicotinamide and inhalation of various high oxygen concentrations have been implemented. Existing methods for assessment of tissue oxygen level are either invasive or insufficient. Accurate and noninvasive means to measure tumor oxygenation are needed for treatment planning, identification of patients who might benefit from oxygenation strategies, and assessing the efficacy of interventions aimed to increase the radiosensitivity of tumors. Of the various imaging techniques used to assess tissue oxygenation, MR spectroscopy and MR imaging are widely available, noninvasive, and clinically applicable techniques. Tumor hypoxia is related closely to insufficient blood flow through chaotic and partially nonfunctional tumor vasculature and the distance between the capillaries and the tumor cells. Information on characteristics of tumor vasculature such as blood volume, perfusion, and increased capillary permeability can be provided with MR imaging. MR imaging techniques can provide a measure of capillary permeability based on contrast enhancement and relative cerebral blood volume estimates using dynamic susceptibility MR imaging. Blood oxygen level dependent contrast MR imaging using gradient echo sequence is intrinsically sensitive to changes in blood oxygen level. Animal models using blood oxygen level-dependent contrast imaging reveal the different responses of normal and tumor vasculature under hyperoxia. Normobaric hyperoxia is used in MR studies as a method to produce MR contrast in tissues. Increased T2* signal intensity of brain tissue has been observed using blood oxygen level-dependent contrast MR imaging. Dynamic blood oxygen level-dependent contrast MR imaging during hyperoxia is suggested to image tumor oxygenation. Quantification of cerebral oxygen saturation using blood oxygen level-dependent MR imaging also has been reported. Quantification of cerebral blood oxygen saturation using MR imaging has promising clinical applications; however, technical difficulties have to be resolved. Blood oxygen level dependent MR imaging is an emerging technique to evaluate the cerebral blood oxygen saturation, and it has the potential and versatility to assess oxygenation status of brain tumors. Upon improvement and validation of current MR techniques, better diagnostic, prognostic, and treatment monitoring capabilities can be provided for patients with brain tumors.
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PMID:Hypoxia imaging in brain tumors. 1268 10

Local hyperthermia of living tissue can cause significant increases in blood flow and oxygenation depending on time-temperature history. Increases in perfusion of the abnormal and insufficient vasculature found in solid tumors may increase tumor oxygenation, thereby increasing the radiation sensitivity of the tumor. We hypothesized that local heating of tumor would increase the oxygenation of the tumor tissue and allow other oxygenating agents to further modify tumor oxygenation and radiation response. In the present study the effect of moderate temperature hyperthermia (MTH) at 41.5-42.5 degrees C for 30-60 min, 250 mg/kg nicotinamide, or carbogen breathing (95% O2/5% CO2) on the radiation sensitivity of FSaII murine fibrosarcomas or R3230 AC rat adenocarcinomas was studied. Individually, these treatments increased the tumor cell sensitivity to single dose 10-15 Gy X-irradiation by 1-5 fold on average, as measured by the in vivo/in vitro tumor excision assay. The combination of tumor MTH with nicotinamide or carbogen breathing increased the radiation sensitivity by 3-5 fold in FSaII tumors and 10-30 fold in R3230 tumors with varying levels of statistical significance. Finally, the triple combination of adjuvant MTH, nicotinamide and carbogen breathing increased the radiation-induced cell death in FSaII tumors to a similar extent as the dual combinations of MTH, nicotinamide or heat, carbogen breathing. However, in R3230 AC tumors the triple adjuvant combination significantly increased radiation-induced cell killing compared to all other dual adjuvant treatments (p < 0.04). To interrogate the mechanism by which heating alters tumor physiology, nitric oxide production in tumor and endothelial cells in culture and tumor tissue after heating was studied. Heating caused an increase in nitric oxide production over a 24 h period after treatment. Subsequently, inhibiting the enzymatic production of NO with L-NAME was found to increase heat-induced growth delay of FSaII tumors. The cause and effect of increased nitric oxide production and the response of the tumor vasculature to heat are discussed in the context of the tumor radiosensitization achieved by heating, carbogen breathing and nicotinamide.
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PMID:Hyperthermic enhancement of tumor radiosensitization strategies. 1613 85

ENOX1 is a highly conserved NADH oxidase that helps to regulate intracellular nicotinamide adenine dinucleotide levels in many cell types, including endothelial cells. Pharmacologic and RNA interference (RNAi)-mediated suppression of ENOX1 impairs surrogate markers of tumor angiogenesis/vasculogenesis, providing support for the concept that ENOX1 represents an antiangiogenic druggable target. However, direct genetic evidence that demonstrates a role for ENOX1 in vascular development is lacking. In this study, we exploited a zebrafish embryonic model of development to address this question. Whole-mount in situ hybridization coupled with immunofluorescence performed on zebrafish embryos demonstrate that enox1 message and translated protein are expressed in most tissues, and its expression is enriched in blood vessels and heart. Morpholino-mediated suppression of Enox1 in Tg(fli1-eGFP) and Tg(flk1-eGFP) zebrafish embryos significantly impairs the development of vasculature and blood circulation. Using in vivo multiphoton microscopy, we show that morpholino-mediated knockdown of enox1 increases NADH levels, consistent with loss of enzyme. VJ115 is a small-molecule inhibitor of Enox1's oxidase activity shown to increase intracellular NADH in endothelial cells; we used VJ115 to determine if the oxidase activity was crucial for vascular development. We found that VJ115 suppressed vasculogenesis in Tg(fli1-eGFP) embryos and impaired circulation. Previously, it was shown that suppression of ENOX1 radiosensitizes proliferating tumor vasculature, a consequence of enhanced endothelial cell apoptosis. Thus, our current findings, coupled with previous research, support the hypothesis that ENOX1 represents a potential cancer therapy target, one that combines molecular targeting with cytotoxic sensitization.
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PMID:The NADH oxidase ENOX1, a critical mediator of endothelial cell radiosensitization, is crucial for vascular development. 2424 17