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At least 505 records · Page 28Linked to original sources
PubMed1998

Vascular density in human melanoma xenografts: relationship to angiogenesis, perfusion and necrosis.

Studies of interrelationships between physiological parameters of tumours are sparse. The possibility that vascular density might be related to the rate of angiogenesis, the rate of perfusion and/or the development of necrosis was examined in the work reported here. Xenografted tumours of four human melanoma cell lines (A-07, D-12, R-18 and U-25) grown orthotopically in BALB/c nu/nu mice were included in the study. Vascular density and fraction of necrotic tissue were determined by stereological analysis of histological sections. The rate of angiogenesis was measured by using the intradermal angiogenesis assay. The rate of perfusion was studied by using the 86Rb uptake method. A-07 showed a higher vascular density, a higher rate of angiogenesis and a higher rate of perfusion than the other lines. D-12, R-18 and U-25, which differed significantly in the rate of angiogenesis, showed similar vascular densities and similar perfusion rates. Consequently, vascular density is not a sensitive measure of the rate of angiogenesis in the melanoma lines studied here, but might adequately reflect the perfusion rate. Significant necrotic regions developed in D-12 and U-25, but not in A-07 and R-18, presumably because large-diameter vessels, possibly arteriovenous shunts, occurred more frequently in D-12 and U-25 than in A-07 and R-18.

Animals↗
PubMed1999

Increased angiogenesis in the uterine cervix associated with human papillomavirus infection.

We studied the relationship between angiogenesis (using the CD34 antibody), the presence of human papilloma virus (HPV) infection, HPV E6 protein expression and the accumulation of p53 protein at various phases of tumour progression in the uterine cervix. Expression of CD34, p53 and HPV E6 protein was evaluated by immunocytochemistry. Presence of the mutant p53 was detected using a mutant specific ELISA, and the type of HPV was determined by the Polymerase Chain Reaction. A total of 230 cervical tissue samples were analyzed and included 40 cases of apparently normal cervical epithelium, 37 low grade squamous intraepithelial lesions (SILs), 43 high grade SILs, 36 well-differentiated squamous cell carcinomas (DSCC), 31 moderately differentiated (MDSCC) and 43 poorly differentiated carcinomas (PDSCC). There was an excellent correlation between the extent of angiogenesis and histological abnormality (r = 0.912, p = 0.000004). The least extent of angiogenesis was seen in normal cervical tissue and low grade SILs where the mean (low power) intra lesional vascular density (ILVD) was 12 +/- 1.13 and 25.66 +/- 5.20, respectively. In high grade squamous intraepithelial lesions (SILs), the mean ILVD value was 80.84 +/- 25.57. In well-differentiated squamous cell carcinomas (WDSCC's) the mean value was 144.22 +/- 28.67 while in moderately differentiated squamous cell carcinomas (MDSCC's) the mean value was 166.29 +/- 34.95 and in poorly differentiated tumours (PDSCC's) 192.42 +/- 27.98. The extent of angiogenesis also correlated to presence of HPV (r = 0.505, p = 0.00001). Increased CD34 expression was associated with the presence of HPV types 16 and 18. A similar correlation was also evident in HPV, 16/18 infected cases expressing the E6 protein (r = 0.612, p = 0.000001). CD34 expression also correlated well with p53 accumulation (r = 0.859, p = 0.000002). Presence of HPV infection significantly correlated with the extent of histological abnormality (r = 0.467, p = 0.00001). Expression of E6 also showed this significant correlation (r = 0.644, p = 0.00002). Accumulation of p53 was significantly more elevated in HPV 16-infected lesions (r = 0.518, p = 0.00001) and E6-expressing cells (r = 0.650, p = 0.000004). Only 12 of the 230 cases analyzed showed presence of the mutant p53 protein. Angiogenesis appears to increase with histological abnormality in the uterine cervix. Angiogenesis also appears to be influenced by high risk HPV infection, the expression of the E6 transforming protein and the p53 tumour suppressor protein.

Antigens, CD34↗
PubMed2000

Prognostic implication of apoptosis and angiogenesis in cervical uteri cancer.

PURPOSE: A retrospective study was performed to investigate the relationship between spontaneous apoptosis and angiogenesis uterine cervix squamous cell carcinoma patients. The prognostic value of each (and both) of these biologic parameters was also tested. METHODS AND MATERIALS: The pathologic materials of 40 cervical uteri squamous cell carcinoma patients were examined and immunohistochemically stained to determine the tumor angiogenesis (tumor microvascular score), using factor VIII-related antigen, and their tumor apoptotic index (AI), using the TdT-mediated dUTP nick end-labeling (TUNEL) method. Three patients were Stage I, 18 were Stage II, 15 were Stage III, and 4 were Stage IV (FIGO classification). All patients were treated with radical radiotherapy and all had follow-up for more than 2 years. RESULTS: The mean AI was 15.1 +/- 12.8, with a median of 8.3. The mean tumor microvascular score was 39.7 +/- 14.4, with a median of 3 8. The patients' age and tumor grade did not seem to significantly affect the prognosis. On the other hand, AI and angiogenesis (tumor microvascular score) were of high prognostic significance. The 3-year disease-free survival (DFS) rate for the patients having AI above the median was 78% (confidence interval [CI] 69-87%), compared to 32% (CI 22-42%) for those having AI below the median. The DFS was 18% (CI 9-27%) for patients having an angiogenesis score above the median, while it was 86% (CI 78-94%) for those patients having a score below the median. CONCLUSION: Determination of both tumor microvascular score and AI can identify patients with the best prognosis of 100% DFS (with low angiogenesis score and high AI). Women with a high score and low AI had the worst prognosis (DFS = 3%, CI 1-5%). Moreover, high AI can compensate partially for the aggressive behavior of tumors showing a high rate of angiogenesis.

Adult↗
PubMed2002

Ionizing radiation modulates the exposure of the HUIV26 cryptic epitope within collagen type IV during angiogenesis.

PURPOSE: The majority of the research on the biologic effects of ionizing radiation has focused on the impact of radiation on cells in terms of gene expression, DNA damage, and cytotoxicity. In comparison, little information is available concerning the direct effects of radiation on the extracellular microenvironment, specifically the extracellular matrix and its main component, collagen. We have developed a series of monoclonal antibodies that bind to cryptic epitopes of collagen Type IV that are differentially exposed during matrix remodeling and are key mediators of angiogenesis. We have hypothesized that ionizing radiation might affect the process of angiogenesis through a direct effect on the extracellular matrix and specifically on collagen Type IV. METHODS AND MATERIALS: Angiogenesis was induced in a chick chorioallantoic membrane (CAM) model; 24 h later, a single-dose treatment with ionizing radiation (0.5, 5, and 20 cGy) was administered. Angiogenesis was assessed, and the exposure of two cryptic regulatory epitopes within collagen Type IV (HUI77 and HUIV26) was studied in vitro by solid-phase ELISA and in vivo by immunofluorescence staining. RESULTS: A dose-dependent reduction of angiogenesis with maximum inhibition (85%-90%) occurring at 20 cGy was demonstrated in the CAM model. Exposure of the cryptic HUIV26 site, an angiogenesis control element, was inhibited both in vitro and in vivo by the same radiation dose, whereas little if any change was observed for the HUI77 cryptic epitope. CONCLUSIONS: A dose-dependent alteration of the functional exposure of the HUIV26 cryptic epitope is induced by radiation in vitro and in the CAM model in vivo. This radiation-induced change in protein structure and function may contribute to the inhibitory effects of ionizing radiation on new blood vessel growth and warrants further studies in other models.

Allantois↗
PubMed2003

Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation.

OBJECTIVES: We examined whether oral folate supplementation would rescue a hypercholesterolemia (HC)-related impairment of ischemia-induced angiogenesis. BACKGROUND: Folate protects against endothelial dysfunction, but the effect of folate supplementation on angiogenesis is little known. METHODS: Sprague-Dawley rats were divided into four groups. Control rats were fed a normal diet (n = 18); HC rats (n = 18) were fed 2% cholesterol diet; and HC + folate (HC+F) rats were fed an HC diet with oral folate (0.003% in water). The left femoral artery and vein were surgically excised, and angiogenesis in the ischemic limb was evaluated. We also examined the effects of Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on angiogenesis in the HC+F state. RESULTS: Laser Doppler blood flow (LDBF) analysis showed lower ischemic/normal LDBF ratio in the HC group than in the control group. Angiographic and histologic analyses on day 14 revealed a smaller angiographic score (p < 0.001) and capillary density (p < 0.001) in the HC group than in controls, which were associated with reduced tissue NOx and cyclic guanosine monophosphate (cGMP) levels. The LDBF ratio, angiographic score, and capillary density were significantly restored in the HC+F group (p < 0.01 vs. HC), which were associated with increased serum folate and tissue NOx and cGMP levels. Finally, L-NAME treatment abolished the beneficial action of folate on angiogenesis in the HC state. CONCLUSIONS: Ischemia-induced angiogenesis was inhibited by HC, which was rescued by oral folate supplementation, at least in part, via an NO-dependent manner.

Administration, Oral↗
PubMed2005

Pathological evaluation of angiogenesis in human tumor.

Angiogenesis is the process in which endothelial cells divide and migrate to form new capillaries, which support the continued growth of tumor through blood flow. Cancer-induced angiogenesis in general represents results of increased expression of angiogenic factors such as VEGF or decreased expression of anti-angiogenic factors, or a combination of both events. Numerous reported studies have demonstrated that angiogenesis plays an important role in tumor progression and metastasis of the great majority of human solid tumors. Furthermore, the quantitation of tumor angiogenesis in resected specimens of human tumor or surgical pathology specimens contribute to assessment of biological behavior and/or clinical outcome of the patients with cancer. Therefore, it is very important to assess the status of angiogenesis or cancer-induced vessels in resected tumor or surgical pathology specimens including those before and after the neoadjuvant therapy. It then becomes very important for pathologists involved in this evaluation to determine which methods to use in order to obtain accurate and reproducible results. In this short review, the status of an analysis of angiogenesis in surgical pathology specimens through analyzing vascular density or vasculatiry using immunohistochemical staining of CD34, a specific immunohistochemical marker for endothelial cells and subsequent evaluation of immunoreactivity in surgical pathology specimens will be summarized.

Animals↗
PubMed2000

The role of VEGF and thrombospondins in skin angiogenesis.

The vasculature in adult skin remains normally quiescent, due to the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. However, skin retains the capacity for brisk initiation of angiogenesis, the growth of new blood vessels from preexisting vessels, during tissue repair and in numerous diseases, including inflammatory skin diseases such as psoriasis and skin cancers such as cutaneous squamous cell carcinomas. Moreover, cyclic vascular expansion occurs during the growth phase of the hair follicle. Recent evidence suggests vascular endothelial growth factor as the major skin angiogenesis factor. During skin angiogenesis, expression of vascular endothelial growth factor is induced in epidermal keratinocytes by several stimuli including transforming growth factor-alpha and hypoxia, leading to increased vascularization of the dermis. In contrast, vascular endothelial growth factor-C induces skin lymphangiogenesis. Thrombospondin-1 and thrombospondin-2 are endogenous inhibitors of angiogenesis that are expressed in normal skin, maintaining the quiescence of cutaneous vessels. Both inhibitors potently inhibit skin cancer growth via inhibition of tumor angiogenesis. Targeting cutaneous blood vessels represents a promising new therapeutic approach for the treatment of a variety of skin diseases.

Adult↗
PubMed2002

Roles of bradykinin in vascular permeability and angiogenesis in solid tumor.

Bradykinin (BK) is involved in tumor angiogenesis. To elucidate the mechanism underlying BK-induced angiogenesis, we evaluated the roles of BK in tumor-associated vascular permeability and angiogenesis in the different phases of tumor development in mice bearing sarcoma 180 cells. The vascular permeability was significantly enhanced in the early growth phase (which peaked at day 5), and was thereafter markedly reduced. By contrast, tumor angiogenesis increased gradually over a 20-day experimental period. Oral administration of a B2 receptor antagonist, FR173657 (30 mg/kg/day), significantly suppressed the vascular permeability, but a B1 antagonist, desArg10-Hoe140 (1 mg/kg/day) did not. An immunohistochemical study revealed the presence of immunoreactive B2 receptor in the endothelial cells in the early phase, whereas B2 receptors were also observed in the stromal fibroblasts in the late phase. We also found that VEGF was detected exclusively in the stromal fibroblasts only in the late phase. Furthermore, VEGF immunoreactivity was attenuated by the treatment with FR173657. Tumor angiogenesis was significantly reduced by treating the tumor tissues with FR173657 both in the early phase (days 1-6, 30 mg/kg/day, oral administration) and in the late phase (days 7-12, 30 mg/kg/day, oral administration), whereas it was inhibited by neutralization with anti-VEGF antibody (1 microg/site/day, local injection) only in the late phase. These results suggest that BK would promote angiogenesis by increasing vascular permeability in the early phase via B2 receptor in the endothelial cells and by promoting up-regulation of VEGF via B2 receptor in the stromal fibroblasts in the late phase.

Animals↗
PubMed2003

Low concentrations of arsenic induce vascular endothelial growth factor and nitric oxide release and stimulate angiogenesis in vitro.

Arsenic (As) is widely distributed in nature, and its contamination in drinking water remains a major public health problem. Exposure to As may lead to degenerative peripheral vascular diseases. The purpose of this study is to clarify the role of As in modulating cell proliferation and in vitro angiogenesis in human umbilical vein endothelial cells (HUVECs) and to scrutinize the contributing factors of these events. The results revealed that lower concentrations (up to 1 microM) of sodium arsenite stimulated HUVEC cell growth. An in vitro angiogenesis assay indicated that low concentrations of As increased vascular tubular formation, which was abrogated by hemoglobin, a potent nitric oxide scavenger. In contrast, higher concentrations of As (>5 micro M) revealed cytotoxicity and inhibition to angiogenesis. We also demonstrated that lower concentrations of As upregulated the expression of constitutive nitric oxide synthase (NOS3) at both transcriptional and translational levels and that lower concentrations of As implicated a modulatory role in vascular endothelial growth factor (VEGF) expression. In addition, low concentrations of As (<1 micro M) increased von Willebrand Factor (vWF) antigen expression, whose elevation paralleled the onset of angiogenesis and was considered an early indicator of endothelial activation in tumor metastasis. VEGF and basic fibroblast growth factor can synergistically upregulate the vWF gene expression. Therefore, we conclude that the treatment of HUVECs with As leads to cell proliferation and activation, which preferentially enhances angiogenesis in vitro, possibly via the VEGF-NOS signaling pathway. The molecular mechanism(s) by which As facilitates angiogenesis remains to be elucidated.

Arsenites↗
PubMed1997

Development of angiogenesis inhibitors for cancer therapy.

Abundant literature exists demonstrating that tumors are dependent on angiogenesis for both tumor growth and invasion. The extent of angiogenesis in primary tumors has been demonstrated to be associated with a negative prognosis in several tumors including non-small cell lung carcinoma, prostate cancer, and in node-negative breast cancer, where angiogenesis is an independent negative prognostic factor. These data demonstrate the significance of angiogenesis in tumor biology and indicate that it can be utilized as a target for novel therapeutic strategies. The recent expansion of knowledge into the specific pathways of tumor angiogenesis has provided reagents which can now be utilized to provide markers of efficacy of antiangiogenic agents in cancer patients. A critical part of the development of angiogenesis inhibitors for cancer therapy is the clinical trial strategy. Since these agents are primarily thought to be cytostatic, carefully designed trials must be conducted which focus on appropriate endpoints and integrate relevant biologic markers to support efficacy.

Antineoplastic Agents↗
PubMed1999

Association of angiogenesis and poor prognosis in node-positive patients receiving anthracycline-based adjuvant chemotherapy.

UNLABELLED: Tumoral angiogenesis has been described as associated with poor prognosis in breast cancer, particularly for node negative breast cancer. The purpose of this study was to evaluate the influence of angiogenesis in node-positive breast cancer and particularly its potential impact on adjuvant chemotherapy. PATIENTS AND METHODS: One hundred and thirty-five node-positive breast cancer patients who received anthracycline or derivative based adjuvant chemotherapy were selected from the data base of the Institut Paoli Calmettes. Angiogenesis was evaluated using CD31 antibody. Other prognosis variables studied were: hormonal status, tumor size, hormonal receptors, Elston and Ellis grade, and number of involved lymph nodes. RESULTS: In multivariate analysis, a high level of angiogenesis was independently associated with a diminution of survival (p = 0.007), and of metastasis-free survival (p = 0.003). Other variables associated with poor survival were progesterone receptor status (p = 0.003) and Elston's grade (p = 0.003), and with metastasis-free survival, progesterone receptor status (p = 0.018). CONCLUSION: Tumoral angiogenesis appears to be an independent prognostic factor for node-positive breast cancer, when treated with adjuvant chemotherapy. Adjuvant strategies for patients with a high level of angiogenesis should be discussed.

Adult↗
PubMed2002

Inflammatory infiltrate, VEGF and FGF-2 contents during corneal angiogenesis in STZ-diabetic rats.

Angiogenesis is a key mechanism that influences several physiological and pathological processes, including wound healing. During the past decades, many groups have shown that controlling angiogenesis might be an answer to overcome pathological situations when this process is out of control. Many altered metabolic states exert considerable influence on the development of angiogenesis. We have chosen diabetes as a model of a progressive metabolic disease with many associated conditions, including an alteration of wound healing dynamics described elsewhere. To evaluate the growth of newly formed blood vessels during diabetes, we induced corneal angiogenesis through silver nitrate cauterization in streptozotocin-induced diabetic rats, always comparing to control non-diabetic or insulin-treated diabetic rats. Computer-aided analysis showed that both the percentage of area taken by vessels on the cornea and their average length were decreased in diabetic animals; furthermore, this diminishment was prevented by insulin treatment in previously diabetic rats. Immunohistochemical staining of neutrophils and macrophages (EDI clone) did not show any differences on number of migrating cells in the cornea. Immunolocalization of vascular endothelial growth factor and basic fibroblast growth factor did not differ considerably among groups either. These results support previous findings that angiogenesis is decreased due to the development of diabetes mellitus but contrasts to descriptions from other investigators in regard to the inflammatory infiltrate and production of growth factors. In our experimental conditions, the cause of the decreased angiogenesis in diabetic rats remains for further elucidation.

Animals↗
PubMed2001

Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes.

Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.

Animals↗
PubMed1998

Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging.

Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin alphaVbeta3, has been shown to correlate with tumor grade. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial alphaVbeta3 via the LM609 monoclonal antibody. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angiogenic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of alphaVbeta3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.

Animals↗
PubMed2004

Regulation of angiogenesis by tissue factor cytoplasmic domain signaling.

Hemostasis initiates angiogenesis-dependent wound healing, and thrombosis is frequently associated with advanced cancer. Although activation of coagulation generates potent regulators of angiogenesis, little is known about how this pathway supports angiogenesis in vivo. Here we show that the tissue factor (TF)-VIIa protease complex, independent of triggering coagulation, can promote tumor and developmental angiogenesis through protease-activated receptor-2 (PAR-2) signaling. In this context, the TF cytoplasmic domain negatively regulates PAR-2 signaling. Mice from which the TF cytoplasmic domain has been deleted (TF Delta CT mice) show enhanced PAR-2-dependent angiogenesis, in synergy with platelet-derived growth factor BB (PDGF-BB). Ocular tissue from diabetic patients shows PAR-2 colocalization with phosphorylated TF specifically on neovasculature, suggesting that phosphorylation of the TF cytoplasmic domain releases its negative regulatory control of PAR-2 signaling in angiogenesis. Targeting the TF-VIIa signaling pathway may thus enhance the efficacy of angiostatic treatments for cancer and neovascular eye diseases.

Animals↗
PubMed2006

A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours.

The present study determined the influence of a retinoid X receptor agonist bexarotene on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with bexarotene inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of bexarotene. Our data showed that bexarotene decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of bexarotene to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of bexarotene in treatment of angiogenesis and metastasis in solid tumours.

Animals↗
PubMed2004

Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy.

Bone marrow (BM) angiogenesis is increased in multiple myeloma and is an important prognostic factor. However, prior studies were mainly done on patients receiving conventional chemotherapy and there is limited data on its prognostic value in patients undergoing high-dose therapy (HDT) as initial therapy. We studied BM angiogenesis in terms of microvessel density (MVD) in 88 newly diagnosed patients, who were uniformly treated, with 3-4 cycles of induction chemotherapy followed by HDT. We examined if MVD at diagnosis was predictive of response to induction therapy or to subsequent HDT. In addition, we also examined its prognostic value in these patients. The median MVD for primary refractory patients was 28 (range, 2-84) compared to 27 (range, 2-99) for responding patients (P=0.7). The median progression-free survival (PFS) was 21 months for those with high-grade angiogenesis compared to 42 months for those with low-grade angiogenesis, P=0.017. The median overall-survival (OS) from diagnosis was 40 months for those with high-grade angiogenesis and not yet reached, for those with low-grade angiogenesis, P=0.007. BM MVD at the time of initial diagnosis is an important prognostic factor for OS and PFS in patients undergoing autologous transplantation as frontline therapy for myeloma.

Adult↗
PubMed2004

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy.

IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN-gamma and angiostatic CXCR3 chemokine ligands. Naked DNA intramuscular injection of an expression vector plasmid producing IL-12 resulted in significant, well-tolerated elevation of serum IL-12 levels. Injection of the IL-12 plasmid at least 2 days, and up to 20 days, before subcutaneous injection of matrigel with angiogenic factors resulted in strong prevention of angiogenesis in both C57/bl and nude mice. A single injection of the IL-12 plasmid contemporarily with the matrigel or 2 days after resulted in partial, statistically not significant, inhibition. Control plasmid injection did not affect either angiogenesis or angiogenesis inhibition by IL-12 protein in vivo. Angiogenesis inhibition was observed in NK cell-depleted C57/bl and nude mice as well as in IFN-gamma(-/-) and CXCR3(-/-) knockout mice, indicating that NK- and/or T-cell-initiated IFN-gamma-chemokine cascades were not involved in the angiogenesis inhibition observed in vivo. Finally, IL-12 plasmid DNA gene transfer significantly prevented the growth and vascularization of highly angiogenic KS-Imm Kaposi's sarcoma and TS/A murine mammary carcinoma tumors in nude and/or syngeneic mice. These data suggest that a preventive gene therapy approach using antiangiogenic cytokines can effectively inhibit tumor angiogenesis and KS, representing an example of angioimmunoprevention.

Animals↗