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

Courses of irradiation consisting of 6000 rad in ten equal fractions over 12 days delivered to KHT sarcomas in mice controlled 55% of the local tumors but 83% of the mice died from metastases. Three strategies to reduce the risk of metastatic spread were tested. The fractionation scheme was changed to deliver the same total dose using a large initial fraction followed by seven equal portions with the same overall time. ICRF-159 was used with the intention of partially synchronizing the tumor growth fraction in a radiosensitive state of the growth cycle and of promoting normalization of the tumor vasculature. Levamisole was used to stimulate the immune system. The combination of ICRF-159 with the eight-fraction radiation course proved to be effective for both increasing local control and decreasing the incidence of metastases. The addition of levamisole did not improve the results obtained with a combination of ICRF-159 and irradiation.
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PMID:The influence of ICRF-159 and levamisole on the incidence of metastases following local irradiation of a solid tumor. 729 76

Eradication of malignant brain tumors by in situ intratumoral, retrovirally mediated transfer of the herpes simplex virus thymidine kinase (HSVtk) gene, which sensitizes the tumor cells to ganciclovir, has recently been demonstrated in animal models. The observation that tumors studied in vitro and in animals can be completely eliminated despite only partial transduction of the tumor suggests a bystander mechanism that affects nontransduced tumor cells. Such a bystander effect is not completely understood and may represent a combination of several factors that lead to tumor eradication. Endothelial cells of the tumor blood vessels were shown to occasionally integrate the retroviral vector and thus become sensitized to ganciclovir. In the presence of vector-producer cells, which continuously release infectious viral particles, diffuse multifocal hemorrhages occurred during ganciclovir administration. When the tumor was composed of cells that had been transduced with the thymidine kinase gene before inoculation, no infectious viral particles were present within the tumor, no transduction of endothelial cells occurred, and no hemorrhages were observed during ganciclovir therapy. These observations suggest that tumor regression may be due, in part, to destruction of in vivo HSVtk-transduced endothelial cells after exposure to ganciclovir, resulting in tumor ischemia as one possible bystander mechanism. The authors investigated this hypothesis using the subcutaneous 9L gliosarcoma tumor model in Fischer rats. The tumors were evaluated with Doppler color-flow and ultrasound imaging during the various phases of the study. Twenty rats received intratumoral injections of HSVtk retroviral vector-producer cells (6 x 10(7) cells/ml) 21 days after bilateral flank tumor inoculation. Ten rats were subsequently treated with intraperitoneal ganciclovir (15 mg/kg/ml twice a day) for 14 days starting on Day 7 after producer cell injection; 10 control rats received intraperitoneal saline injections (1 ml twice a day) instead of ganciclovir. Ultrasound and flow images were obtained before cell injection, before and during ganciclovir or saline administration, and after cessation of treatment. The number, location, and ultrasonographic appearance of tumor vessels and the tumor volumes were recorded. The number of blood vessels in the tumors increased over time in both groups before treatment. Intratumoral cell injection without ganciclovir administration did not influence tumor growth or intratumoral vasculature. However, tumor vasculature decreased after initiation of ganciclovir therapy in the HSVtk-transduced tumors (p < 0.05). Early patchy or diffuse necrotic changes associated with ultrasonographic evidence of scattered intratumoral hemorrhage occurred in tumors treated with ganciclovir.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of thymidine kinase transduction and ganciclovir therapy on tumor vasculature and growth of 9L gliomas in rats. 802 10

Interleukin-2 and hyperthermia have been used individually to treat a variety of tumors in both experimental and human trials. Combined adoptive immunotherapy and hyperthermia is an exciting new line of investigation. Previous work in our laboratory has shown that combined local hyperthermia and rIL-2 therapy can significantly decrease the rate of tumor growth. In this study, we investigated the effect of combined whole-body hyperthermia (WBHT) and rIL-2 on the growth of subcutaneous MCA-105 murine tumors in C57BL/6 mice. Treatment of both microscopic (day 3) and macroscopic (day 10) tumors was evaluated. In the treatment of microscopic tumors, animals received either no treatment; rIL-2 (3 x 10(5) IU ip tid) on days 3-7; plus WBHT (41 degrees C for 30 min) on days 3, 5, and 7; or WBHT only days 3, 5, and 7. In treating macroscopic tumors, animals received either no treatment; rIL-2 on days 10-14; plus WBHT on days 10, 12, and 14; or WBHT only on days 10, 12, and 14. While combined treatment and WBHT alone had no significant effect on the growth of microscopic tumors, combined IL-2 and WBHT significantly reduced the rate of tumor growth of macroscopic tumors. These results suggest that the tumor microenvironment plays a critical role in combined WBHT and rIL-2 therapy, and may be due to effects of WBHT on the tumor vasculature.
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PMID:Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma. 833 40

Flavone acetic acid (FAA) causes regression of a range of slow growing solid tumors implanted subcutaneously in mice. Although its precise mechanism of action is unknown, vascular collapse has been shown to precede tumor growth delay and regression. The aim of this study was to determine whether or not endothelial cell function was directly affected by clinically relevant concentrations of FAA. FAA at 100-250 micrograms/ml inhibited endothelial cell proliferation in vitro, but did not compromise cellular function or viability. FAA abolished tubule formation in an in vitro angiogenesis assay and reduced vascular development of the chick embryo chorioallantoic membrane. In addition to targeting established tumor vasculature, FAA may also affect proliferating endothelium which may be involved in mediating the reduced tumor growth rate or stasis often often observed after drug exposure. The chorioallantoic membrane of the chick embryo may represent an important model to elucidate more clearly the effect of FAA on a growing vascular network.
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PMID:Effect of flavone acetic acid on endothelial cell proliferation: evidence for antiangiogenic properties. 861 48

The diagnostic value of fluorescein angiography (FA) in the evaluation of small suspected choroidal melanomas is limited. Indocyanine green videoangiography (ICGV) has overcome some of the problems of FA in the imaging of normal and abnormal choroidal vessels. This study was performed to reveal the role of ICGV in the detection of the intrinsic tumor vasculature of choroidal malignant melanomas. A total of 24 patients with posterior-segment malignant melanoma underwent FA and ICGV using the scanning laser ophthalmoscope. All patients were grouped into 1 of 2 categories, depending on the tumor elevation: group I 10 patients with lesions elevated to < 4 mm, and group II 14 patients with lesions measuring > 4 and < 8 mm in height. On early frames of the ICGV the borders of the tumors were better demarcated from the background and the tumors appeared larger in the basal dimension than with FA or clinical examination. ICGV was superior to standard FA in imaging intrinsic tumor vasculature. Abnormal vasculature features included different caliber size, tortuosities, corkscrew loops, irregular ramifications, and irregular staining of the vessel walls. These intrinsic tumor vessels were identified in 6 of 10 patients from group I and in 12 of 14 patients from group II. ICGV appears to add some information in the diagnosis and documentation of tumor growth. It may allow detection of pathologic tumor vessels that cannot be detected by standard FA. The borders of the tumor are better demarcated against the background by ICGV than by FA or clinical examination.
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PMID:Indocyanine green videoangiography of malignant melanomas of the choroid using the scanning laser ophthalmoscope. 864 81

Tumor blood flow (TBF) is characterized by spatial and temporal heterogeneities. Despite the crucial role of TBF in tumor growth, metastasis, and therapy, the mechanisms underlying these heterogeneities are not fully understood. Tumor vessels are, in general, more leaky than normal vessels and this may enhance the efficiency of fluid exchange between the vascular and the interstitial space. The coupling between transvascular fluid exchange and hemodynamics in tumors has not been explored previously. To investigate the role of transvascular fluid exchange on afferent and efferent blood flow, we modeled the tumor vasculature as an equivalent single vessel which is permeable and deformable and embedded in a fluid medium with uniform pressure. Simulations were carried out to examine the effects of vessel leakiness, vessel compliance, and interstitial fluid pressure on (a) pressure-flow relationship, (b) arterial-venous pressure relationship, and (c) pressure profile along the vessel. Experiments suggested by model simulations required an independent control of arterial and venous pressure and tumor blood flow. To this end, we perfused tissue-isolated tumors ex vivo and obtained data on perfusate flow rate vs arterial and venous pressures. The simulations predicted the following trends as a result of an enhanced fluid filtration across the vessel wall: (a) for a fixed arterial-venous pressure difference, efferent flow decreases with increasing venous pressure, (b) changes in venous pressure are not completely transmitted to the arterial side, and (c) the pressure profile along the vessel becomes less steep. The experimental results confirmed these trends and indicated that vascular and interstitial flow are coupled in isolated tumors. The implications of this coupling for the spatial and temporal heterogeneity in TBF are discussed.
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PMID:Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity. 881 51

Human Burkitt lymphoma cell lines give rise to progressively growing subcutaneous tumors in athymic mice. These tumors are induced to regress by inoculation of Epstein-Barr virus-immortalized normal human lymphocytes. In the present study, analysis of profiles of murine cytokine/chemokine gene expression in Burkitt tumor tissues excised from the nude mice showed that expression of the murine alpha-chemokine interferon-inducible protein-10 (IP-10) was higher in the regressing than in the progressive Burkitt tumors. We tested the effects of IP-10 on Burkitt tumor growth in nude mice. Inoculation of established Burkitt tumors either with crude preparations of murine IP-10 or with purified human IP-10 caused visible tumor necrosis in a proportion of the animals, although no complete tumor regressions were observed. Constitutive expression of murine IP-10 in Burkitt cells reduced their ability to grow as subcutaneous tumors, and caused visible tumor necrosis in a proportion of the animals. Histologically, IP-10-treated and IP-10-expressing Burkitt tumors had widespread evidence of tumor tissue necrosis and of capillary damage, including intimal thickening and vascular thrombosis. Thus, IP-10 is an antitumor agent that promotes damage in established tumor vasculature and causes tissue necrosis in human Burkitt lymphomas established subcutaneously in athymic mice.
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PMID:Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo. 894 14

The therapy of solid tumors with conventional chemotherapeutics, drug delivery preparations and immunomodulatory agents directed against the tumor cells is corrupted by a major barrier presented by the tumor vasculature. Permeability of the tumor blood vessels for transport of small molecules and macromolecular drug-carrier conjugates is only sufficient in the blood vessels at the tumor-host interface. Downregulation of the expression of adhesion molecules, required for the facilitation of immune cell recruitment, by the tumor vascular endothelium results in an escape of the tumor from host defence. New therapeutic approaches for the treatment of solid tumors are aimed at the tumor vasculature, either at the endothelial cells themselves or at basement membrane or tumor stroma components. Angiogenesis can be directly blocked with angiogenesis inhibitors, while angiogenesis related factors can serve as tumor vasculature specific epitopes for drug delivery strategies. Some glycoproteins expressed by tumor endothelial cells or present in the basement membrane and tumor stroma are also potential tumor selective targets. Therapeutic modalities that are suitable for site specific delivery are agents that increase tumor accumulation of (targeted) chemo/radiotherapeutics through increasing tumor vascular permeability. The observation that for tumor growth the blood supply is a limiting factor, led to the development of strategies to inhibit angiogenesis or block the tumor blood flow. Manipulation of the expression of endothelial cell adhesion molecules by selectively delivering modulatory agents at or in the tumor vascular endothelial cells may induce (bispecific antibody mediated) host defense activity directed against the tumor cells.
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PMID:Tumor vascular endothelium: barrier or target in tumor directed drug delivery and immunotherapy. 903 14

Compelling data implicate angiogenesis and tumor-associated neovascularization as a central pathogenic step in the process of tumor growth, invasion, and metastasis. These complex processes involve multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature, and the surrounding extracellular tissue matrix. A tumor remains in a dormant state, the cellular proliferation rate balanced by the apoptotic rate, unable to grow in size beyond a few millimeters in the absence of the acquired angiogenic phenotype. The mechanism by which tumors switch to the angiogenic phenotype is unknown. Therapeutic agents and strategies are being devised either to interrupt or inhibit one or more of the pathogenic steps involved in the process of tumor neovascularization or to directly target and destroy the tumor vasculature. Therapies affecting an end target or pathway that cannot be circumvented by alternate mechanisms may significantly enhance efficacy and broaden applicability. These approaches may result in small, avascular tumors maintained in a dormant state or, perhaps in combination with cytotoxic therapies, they may potentiate shrinkage of tumors to, and maintain them, in a dormant state. As more powerful antiangiogenic agents are developed, perhaps even these dormant microscopic foci may be eradicated. Antiangiogenesis agents and strategies differ from the usual cancer therapeutic approaches; therefore, investigators must devise new paradigms for the clinical development of agents that may only have a static effect on tumors and require prolonged, chronic administration. Methods to assess the in vivo biologic activity of these compounds in patients are needed. Ultimately, antiangiogenic therapy may provide an additional novel cancer treatment suitable for combination with standard therapies.
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PMID:Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies. 912 90

Tumor-derived vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) plays an important role in neovascularization and the development of tumor stroma. Furthermore, VEGF receptors are over-expressed in the endothelial cells of tumor vasculature and almost non-detectable in the vascular endothelium of adjoining normal tissues. The differential expression of receptor offers a selective advantage for targeting cytotoxic toxin polypeptides. We have prepared a vascular targeting reagent by chemically linking recombinant VEGF to a truncated form of diphtheria toxin. The VEGF-toxin conjugate was selectively toxic to endothelial cell lines and inhibited experimental neovascularization of the chick chorioallantoic membrane. In the present study, we examined the effects of VEGF-toxin conjugate on solid tumor growth. Athymic nude mice with established subcutaneous tumors were treated with daily intraperitoneal injections of the VEGF-toxin conjugate or free toxin. When compared with control animals treated with the toxin polypeptide alone, the conjugate-treated animals displayed a significant inhibition of tumor growth. Histological analysis of tumors from conjugate-treated animals revealed hemorrhagic necrosis consistent with a vascular-mediated injury. In contrast, highly vascularized normal tissues from conjugate-treated animals demonstrated no evidence of hemorrhage or tissue injury. The conjugate was well tolerated without apparent toxicities. Our results illustrate the anti-tumor activity of a VEGF-toxin conjugate selectively targeting the tumor neovasculature.
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PMID:Targeting the tumor vasculature: inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate. 939 67


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