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)

Targeting tumor cells or tumor vasculature by peptides is a promising strategy for delivering cytotoxic drugs for cancer therapy. The identification of efficient targeting peptides depends on the availability of informative methods for determining cellular binding specificities. Here, we have used fluorescence-activated cell-sorting (FACS) analysis in combination with an isopentane freezing method to show targeted binding of the Arg-Gly-Asp (RGD)-4C-peptide labeled with FITC, not only to endothelial cells but also to tumor cells in human breast cancer xenografts grown in nude mice. Nontumorous cells showed only background binding. This study suggests, that the RGD-4C-peptide can target tumor endothelial cells as well as tumor cells. Consequently, it should be possible to design a combination therapy approach against both targets.
Cancer Res 2002 Sep 15
PMID:Arginine-glycine-aspartic acid (RGD)-peptide binds to both tumor and tumor-endothelial cells in vivo. 1223 75

Recognition of the dependence of solid tumor growth on the formation of new blood vessels has ignited an enormous research effort aimed at the development of new therapeutic strategies for cancer. Besides direct application of drugs inhibiting endothelial cell function during angiogenesis, tumor vasculature directed drug-targeting strategies have been investigated for this purpose. In animal models of disease, proof of principle regarding the potential of selective interference with tumor blood flow as a powerful tumor therapy has been generated to its full extent. The challenge for the coming years will be to develop these strategies into clinically applicable ones. New insights into the molecular mechanisms prevailing in the endothelium during angiogenesis and into the mechanism(s) of action of drugs with anti-angiogenic activities, as well as new techniques to identify useful tumor endothelium specific target epitopes have in recent years been exploited to meet this challenge. This review summarizes vasculature directed therapeutic strategies proven to be successful in pre-clinical models and new (drug targeting) technologies enabling the development of more effective therapeutics for the treatment of cancer.
Pharm Res 2002 Sep
PMID:Tumor vasculature directed drug targeting: applying new technologies and knowledge to the development of clinically relevant therapies. 1240 59

The development and growth of solid tumors rely on a process known as perfusion which allows for the delivery and clearance of nutrients through their vasculature. The classical approach of studying tumor vasculature by histologic staining of endothelial cells provides a measure of microvessel density in areas of high vascularization (so-called "hot spots"). More advanced high-resolution, parametric, contrast-enhanced MRI techniques enable quantitative assessment of the vascular distribution and function over the entire tumor. Hence, MRI overcomes the intratumoral variation of the histological method. Clinical testing of the MRI approach, that evaluates the permeability and surface area of the tumor vasculature, demonstrates improved accuracy of breast cancer diagnosis.
J Exp Clin Cancer Res 2002 Sep
PMID:Magnetic resonance imaging of breast cancer angiogenesis: a review. 1258 54

A multifocal mouse liver tumor model chemically induced with 5,9-dimethyl-7H-dibenzo[c,g]carbazole was investigated by respiratory-triggered morphological and functional MRI (fMRI) at 4.7 Tesla. The model is characterized by the presence of two tumor types: hypovascular cholangioma and vascularized hepatocellular carcinoma (HCC). Growth curves measured by 3D-MRI showed limited growth of cholangiomas and rapid growth of HCCs after a latency of about 25 weeks. Functional imaging based on T(2) (*)-weighted fast gradient-echo MRI and carbogen breathing was optimized for liver imaging in mice. A response to carbogen was observed in HCCs but not in cholangiomas. Transversal analysis (50 HCCs) of signal change upon carbogen revealed four different types of response patterns: 1) signal increase upon carbogen administration (74%); 2) small or insignificant signal change (10%), 3) transient signal decrease and delayed increase (8%), and 4) signal decrease (8%). Longitudinal follow-up of a subgroup (N = 17) showed that an initially observed type 1 response, attesting to the presence of a functional vasculature, remained stable for at least 3 weeks in 14 HCCs. A switch from a type 1 response to another response type may be useful for demonstrating, in a noninvasive manner, a disturbance of tumor vasculature induced by anti-vascular or anti-angiogenic therapy.
Magn Reson Med 2003 Sep
PMID:Morphological and carbogen-based functional MRI of a chemically induced liver tumor model in mice. 1293 60

We describe an approach employing intramuscular plasmid electrotransfer to deliver secretable forms of K1-5 and K1-3-HSA (a fusion of K1-3 with human serum albumin), which span, respectively, five and three of the five kringle domains of plasminogen. A tetracycline-inducible system (Tet-On) composed of three plasmids coding, respectively, for the transgene, the tetracycline transcriptional activator rtTA, and the silencer tTS was employed. K1-3-HSA and K1-5, produced from C2C12 muscle cells, were found to inhibit endothelial cell (HMEC-1) proliferation by 30 and 51%, respectively. In vivo, the expression of the transgene upon doxycycline stimulation was rapid, stable, and tightly regulated (no background expression) and could be maintained for at least 3 months. Blood half-lives of 2.1 and 3.7 days were found for K1-5 and K1-3-HSA, respectively. The K1-5 protein was secreted from muscle into blood at a level of 45 ng/ml, which was sufficient to inhibit MDA-MB-231 tumor growth by 81% in nude mice and B16-F10 melanoma cell lung invasion in C57BL/6 mice by 73%. PECAM-1 immunostaining studies revealed modest tumor vasculature in mice expressing K1-5. In contrast, K1-3-HSA, although secreted into blood at much higher level (250 ng/ml) than K1-5, had no effect on tumor growth.
Mol Ther 2003 Sep
PMID:Coelectrotransfer to skeletal muscle of three plasmids coding for antiangiogenic factors and regulatory factors of the tetracycline-inducible system: tightly regulated expression, inhibition of transplanted tumor growth, and antimetastatic effect. 1294 15

TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of antimicrotubule agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.
Cancer Sci 2003 Sep
PMID:Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo. 1296 83

Blood-borne therapeutics, which rely on diffusion and convection for delivery, often do not accumulate in effective concentrations distant from vasculature and are therefore unable to eradicate all cells within a tumor. Motile bacteria have the potential to overcome the diffusion and pressure gradients that prevent passive materials from penetrating into poorly perfused regions of tumors. Here, we test several proposed mechanisms of Salmonella typhimurium accumulation in tumors, including: (a) entrapment in the chaotic vasculature of tumors; (b) attraction to specific tumor microenvironments; and (c) preferential replication within specific microenvironments. After systemic injection of S. typhimurium into tumor-bearing mice, we used intravital microscopy and histological techniques to quantify their interaction with tumor vasculature. Immediately after injection, few S. typhimurium (<4 in 10,000) adhered to tumor vasculature; most remained passively suspended in the blood. Despite this low initial adhesion, approximately 10,000-fold more S. typhimurium accumulated in tumors than any other organ 1 week after the injection, thus demonstrating their specificity. However, within the tumors, we found that most bacteria were located in necrotic tissue as large colonies far (750 micro m) from functional vasculature. Together, these results suggest that S. typhimurium has limited ability to adhere to tumor vasculature and migrate within tumors and only survives in tissue that becomes necrotic. Although S. typhimurium is a promising delivery vehicle because of its tumor specificity, increasing its intra-tumoral motility should improve its therapeutic effectiveness.
Cancer Res 2003 Sep 01
PMID:Sparse initial entrapment of systemically injected Salmonella typhimurium leads to heterogeneous accumulation within tumors. 1450 Mar 42

Recently, we observed that dietary feeding of silibinin strongly prevents and inhibits the growth of advanced human prostate tumor xenografts in athymic nude mice without any apparent signs of toxicity together with increased secretion of insulin-like growth factor-binding protein 3 from the tumor in to mouse plasma (R. P. Singh et al., Cancer Res., 62:3063-3069, 2002). In the present study, we investigated the effect of silibinin feeding [0.05% and 0.1% (w/w) in diet for 60 days] on the prognostic biomarkers (namely, proliferation, apoptosis, and angiogenesis) in the prostate tumor xenografts of the above-reported study. Immunohistochemical analysis of the tumors for proliferating cell nuclear antigen and Ki-67 showed that silibinin decreases proliferation index by 28-60% and 30-60% (P<0.001) as compared with their controls, respectively. In situ detection of apoptosis by terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling staining of tumors showed a 7.4-8.1-fold (P<0.001) increase in apoptotic cells in silibinin-fed groups over that of control group. Silibinin also increased activated caspase 3-positive cells by 2.3-3.6-fold (P<0.001). CD31 staining for tumor vasculature showed a significant decrease (21-38%; P<0.001) in tumor microvessel density in silibinin-fed groups of tumors as compared with control group of tumors. Tumor sections were also analyzed for vascular endothelial growth factor and insulin-like growth factor-binding protein 3 protein expression, and a slightly decreased and a moderately increased cytoplasmic immunostaining in silibinin-fed groups were observed as compared with the control group, respectively. Together, these results suggest that inhibition of advanced human prostate tumor xenograft growth in athymic nude mice by silibinin is associated with its in vivo antiproliferative, proapoptotic, and antiangiogenic efficacy in prostate tumor.
Cancer Epidemiol Biomarkers Prev 2003 Sep
PMID:Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. 1450 8

Bromodeoxyuridine (BrdUrd) is used extensively to measure the fraction of proliferating cells in tumors. Unlike endogenous markers of proliferation such as proliferating cell nuclear antigen (PCNA) and Ki-67, BrdUrd is exogenously administered and reaches the tumor via vasculature where it must then diffuse throughout the tissue to label S-phase cells. In this study, we examine the dose dependence of BrdUrd on the tumor distribution of labeled cells in histological sections. Analysis of the distribution of labeled cells in SiHa tumor xenografts showed that a dose between 400 and 1000 mg/kg was required to label cells 150 micro m from blood vessels, approaching the border of necrosis. Lower doses resulted in only the cells close to blood vessels being labeled. Interestingly, cells residing furthest from blood vessels still labeled albeit at half the level of cells situated proximal to the tumor vasculature. Results were compared with the penetration of BrdUrd seen in vitro using multilayered cell culture (MCC), a three-dimensional tissue culture model of solid tumors. Using MCC, an exposure of 100 micro M BrdUrd for 1 h was required for labeling of S-phase cells 150 micro m into the tissue, whereas cells adjacent to the edge of the tissue could be adequately labeled with just 5 micro M BrdUrd for 1 h. The area under the curve for a 100 mg/kg BrdUrd dose in mice was found to be approximately 30 micro M x h.
Cancer Res 2003 Sep 15
PMID:Tumor distribution of bromodeoxyuridine-labeled cells is strongly dose dependent. 1452 88

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6-24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6-72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.
Int J Cancer 2004 Sep 10
PMID:Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis. 1523 40


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