Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.
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PMID:Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. 954 82

Vascular endothelial growth factor (VEGF) is thought to take an important role in tumor angiogenesis. The present study examined VEGF expression immunohistochemically in hepatocellular carcinomas (HCCs) in various histological grades and sizes. In HCCs that were composed of cancerous tissues of single histological grade, VEGF expression was the highest in well-differentiated HCCs, followed by moderately differentiated HCCs, and then poorly differentiated HCCs. VEGF positivity gradually decreased with the increase in tumor size. In the nodules larger than 3.0 cm, 36.8% were VEGF-negative. In HCCs consisting of cancerous tissues of two different histological grades, the expression was less intensive in the higher-grade HCC component. VEGF was not expressed in sarcomatous areas, while VEGF was expressed in the surrounding HCC tissues. The expression was also remarkable in the noncancerous tissues in which inflammatory cell infiltration was apparent. VEGF expression was also examined in six HCC cell lines. In reverse-transcription polymerase chain reaction (RT-PCR) analysis, expressions of the two secretion types (VEGF121 and VEGF165) were the highest. Thus, VEGF protein in culture supernatant was measured by using enzyme-linked immunosorbent assay (ELISA) with or without inflammatory cytokines, i.e., interleukin (IL)-1beta, interferon (IFN)-alpha, IFN-gamma, and tumor necrosis factor (TNF)-alpha; and growth factors, i.e., epidermal growth factor (EGF), platelet-derived growth factor (PDGF)-BB, basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-alpha. As a result, secretion of VEGF from the cell lines was upregulated at various degrees. Based on these findings, VEGF expression in HCC tissues was thought to be related to the histological grade. The findings also indicate that various cytokines and growth factors could cooperatively act to enhance VEGF expressions in HCC.
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PMID:Expression of vascular endothelial growth factor in human hepatocellular carcinoma. 965 98

In this study, we investigated the effects of human type I consensus interferon (IFN-con1) (Amgen) gene transfer into body cavity-based lymphomas (BCBL)-1 cells, which are latently infected with Kaposi's sarcoma-associated herpesvirus (KSHV) human herpesvirus-8 (HHV-8). Both the basal and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-stimulated production of KSHV/HHV-8 mature virions was strongly inhibited in genetically modified IFN-producing BCBL-1 cells as compared with parental or control transduced counterparts. A similar inhibition was obtained on treatment of parental BCBL-1 cells with exogenous IFN-con1. The reduction in KSHV/HHV-8 production was associated with a decrease in the basal and TPA-stimulated intracellular amount of the linear form of the viral genome. Interestingly, 25%40% of the IFN-producing BCBL-1 cell population underwent spontaneous apoptosis in vitro. TPA treatment, which did not significantly affect the viability of the parental and control BCBL-1 cells, resulted in the apoptotic death of up to 70% of the IFN-producing cell population. Addition of exogenous IFN-con1 to parental BCBL-1 cells produced similar effects, although less intense. Injection of either parental or control-transduced BCBL-1 cells into SCID mice resulted in progressively growing tumors characterized by an unusually high level of tumor angiogenesis. In contrast, complete tumor regression was observed in all the mice injected either subcutaneously (s.c.) or intraperitoneally (i.p.) with the IFN-producing BCBL-1 cells. These results represent the first evidence that type I IFN can counteract the activation of a productive herpesvirus infection in latently infected tumor cells by the induction of apoptosis, providing an interesting link between the antiviral and antitumor activities of this cytokine. These data suggest the possible advantages of strategies of type I IFN gene transfer (with respect to the use of the exogenous cytokine) for the treatment of patients with some HHV-8-induced malignancies.
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PMID:Type I consensus IFN (IFN-con1) gene transfer into KSHV/HHV-8-infected BCBL-1 cells causes inhibition of viral lytic cycle activation via induction of apoptosis and abrogates tumorigenicity in sCID mice. 1057 24

We developed an in vivo gene therapy approach to characterize and optimize the anti-angiogenic activity of class I interferons (IFNs), using packaging cell lines producing an amphotropic LXSN-based retrovirus expressing either IFN-alpha1 (alpha1Am12), IFN-beta (betaAm12) murine cDNAs, or the vector alone (neoAm12). Pretreatment of endothelial-like Eahy926 cells in vitro with conditioned media (CM) from alpha1Am12 or betaAm12 cells for 48 hours significantly inhibited their migration and invasion as compared to neoAm12-CM-treated cells. betaAm12-CM also inhibited the formation of capillary-like structures on Matrigel by EAhy926 cells. In vivo, inclusion of the betaAm12 cells strongly inhibited, and alpha1Am12 partially inhibited, the angiogenic response in the Matrigel sponge model in both immune-competent and athymic nude mice. Electron microscopy showed a reduction of host cell infiltration in alpha1Am12- and betaAm12-containing sponges and reduction of invading tubular clefts of host cells as compared to controls. Finally, inoculation of either alpha1Am12 or betaAm12 cells (10%) along with a highly angiogenic Kaposi's sarcoma cell line (90%) resulted in a powerful reduction of tumor growth in nude mice in vivo, as did infection with the interferon-alpha-producing retroviruses. These data suggest that a gene therapy approach using class I interferons can effectively inhibit tumor angiogenesis and growth of vascular tumors.
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PMID:Inhibition of angiogenesis and vascular tumor growth by interferon-producing cells: A gene therapy approach. 1075 62

We describe 2 cases of angioblastoma, a rare, destructive pediatric tumor, treated with interferon alfa 2b (IFNalpha2b). The first patient is a 10-month-old male who presented with an ulcerated palatal neoplasm that could not be completely resected. The second is a male neonate with a congenital tumor of the right hand that invaded the hypothenar eminence, destroying the fourth and fifth metacarpals. Biopsy in both patients was interpreted as giant cell angioblastoma. Angioblastoma is rare; there is only 1 reported case that necessitated amputation of an upper extremity, also initially recommended for our patient. Because there is little experience with chemotherapy, permission was granted to employ an antiangiogenic regimen of IFNalpha2b. The angiogenic protein, basic fibroblast growth factor (bFGF), was abnormally elevated in both patients. Both patients received IFNalpha2b. In the first child, it was used after incomplete resection, because biopsy-proven tumor was present at the margin and in the nasopharynx. Biopsies 15 months after initiation of IFN2alphab were negative for tumor. Therapy was stopped after 3 years. Eighteen months later, the patient remains disease-free. In the second child, IFNalpha2b was started after debridement of the ulcerated tumor. Over 11 months, the tumor completely regressed and there was bony regeneration of the metacarpals. The fifth digit was amputated because of damage to the metacarpophalangeal joint by the tumor. IFNalpha2b therapy was discontinued after 1 year of treatment, and the child remains disease-free 2 years and 8 months later. In conclusion, this report demonstrates that: 1) a bFGF-overexpressing low-grade tumor can respond to IFNalpha2b in a manner similar to life-threatening infantile hemangiomas, 2) urinary bFGF levels can help guide IFNalpha dosage in such patients, and 3) although bFGF-mediated tumor angiogenesis is inhibited by IFNalpha, physiologic angiogenesis seems to be unaffected.
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PMID:Successful antiangiogenic therapy of giant cell angioblastoma with interferon alfa 2b: report of 2 cases. 1182 47

Thymidine phosphorylase (TP) regulates intracellular thymidine metabolism. It has been reported to be a prognostic factor for tumor angiogenesis and to activate some prodrugs of 5-fluorouracil (5-FU) to 5-FU. There is also evidence that TP is induced by interferons (IFNs) and xenobiotics, such as cyclophosphamide and taxanes, in experimental human cancer cells and xenografts. We investigated the induction of TP expression by IFNalpha and Paclitaxel in vitro and in vivo in human tumor cells with low and with high TP activity. TP activity in KB, NUGC-3, and KOC2S cells, which had low TP activity, was increased 2 to 4 fold by IFNalpha, but was still lower than in non-treated SHIN-3 and HRA cells, which have high TP activity. IFNalpha did not promote TP activity in SHIN-3 and HRA cells, but expression of TP mRNA increased 2 to 4 fold in response to IFNalpha in all cells tested. These results suggest that the expression of TP protein would be regulated post-transcriptionally by another factor after IFN-induced amplification of TP mRNA. A single dose of Paclitaxel to nude mice xenografted with KB and KM20C tumors, expressing low TP activity, increased TP activity about 4 to 7 fold compared to non-treated tumors. In contrast, TP expression in MX-1 and H-31 tumors was originally high and did not change by the treatment of Paclitaxel. The activities of uridine phosphorylase in all tumors used showed no changes in response to IFNalpha or Paclitaxel. We determined the level of STAT1alpha, an IFN-inducible transcription factor of the TP gene, and found that it was low in low TP expressing tumor cells and markedly increased to about 4 fold by IFN, almost reaching the level in high TP expressing cells whose STAT1alpha level was unchanged by IFN. When TP activity and STAT1alpha expression in clinically resected colorectal cancers were simultaneously measured, almost all tumors had high expression of both TP and STAT1alpha. In conclusion, our results suggest that IFN and Paclitaxel affect human cancer cells with low TP activity but not those with high TP activity and that the STAT1alpha expression may reflect TP activity, at least in experimental human cancer cells.
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PMID:Induction of thymidine phosphorylase by interferon and taxanes occurs only in human cancer cells with low thymidine phosphorylase activity. 1235 57

T cells responsive to minor histocompatibility (H) antigens are extremely effective in curing leukemia but it remains unknown whether they can eradicate solid tumors. We report that injection of CD8(+) T cells primed against the immunodominant H7(a) minor H antigen can cure established melanomas in mice. Tumor rejection was initiated by preferential extravasation at the tumor site of interferon (IFN)-gamma-producing H7(a)-specific T cells. Intratumoral release of IFN-gamma had two crucial effects: inhibition of tumor angiogenesis and upregulation of major histocompatibility complex (MHC) class I expression on tumor cells. Despite ubiquitous expression of H7(a), dissemination of a few H7(a)-specific T cells in extralymphoid organs caused neither graft-versus-host disease (GVHD) nor vitiligo because host nonhematopoietic cells were protected by their low expression of MHC class I. Our preclinical model yields unique insights into how minor H antigen-based immunotherapy could be used to treat human solid tumors.
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PMID:T cells targeted against a single minor histocompatibility antigen can cure solid tumors. 1622 89

"Differentiation therapy" provides a unique and potentially effective, less toxic treatment paradigm for cancer. Moreover, combining "differentiation therapy" with molecular approaches presents an unparalleled opportunity to identify and clone genes mediating cancer growth control, differentiation, senescence, and programmed cell death (apoptosis). Subtraction hybridization applied to human melanoma cells induced to terminally differentiate by treatment with fibroblast interferon (IFN-beta) plus mezerein (MEZ) permitted cloning of melanoma differentiation associated (mda) genes. Founded on its novel properties, one particular mda gene, mda-7, now classified as a member of the interleukin (IL)-10 gene family (IL-24) because of conserved structure, chromosomal location, and cytokine-like properties has become the focus of attention of multiple laboratories. When administered by transfection or adenovirus-transduction into a spectrum of tumor cell types, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) induces apoptosis, whereas no toxicity is apparent in normal cells. mda-7/IL-24 displays potent "bystander antitumor" activity and also has the capacity to enhance radiation lethality, to induce immune-regulatory activities, and to inhibit tumor angiogenesis. Based on these remarkable attributes and effective antitumor therapy in animal models, this cytokine has taken the important step of entering the clinic. In a Phase I clinical trial, intratumoral injections of adenovirus-administered mda-7/IL-24 (Ad.mda-7) was safe, elicited tumor-regulatory and immune-activating processes, and provided clinically significant activity. This review highlights our current understanding of the diverse activities and properties of this novel cytokine, with potential to become a prominent gene therapy for cancer.
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PMID:mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. 1646 4

Melanoma is a hypervascular tumor and angiogenesis plays a critical role in the development/progression of metastases. As various pathways are involved in tumor angiogenesis, a combination of agents with different antiangiogenesis activities is a reasonable approach. To determine the efficacy and toxicity of combination treatment with low-dose thalidomide and low-dose interferon (IFN) in patients with stage IV melanoma who failed prior treatment(s), fifteen patients with metastatic melanoma (nine cutaneous, six uveal) received oral thalidomide (200 mg daily) with subcutaneous interferon (IFN)-alpha2b (3 MIU, 3x/week). Stabilization or regression of metastases (as evidenced by computed tomographic measurement) was the primary endpoint of the study. Patients were evaluated monthly for toxicity and every 2 months for clinical response. At a median follow-up of 22.8 months (range, 12-32 months), one patient with metastatic cutaneous melanoma achieved partial response, three patients achieved stable disease (one uveal, two cutaneous), nine patients progressed, and two were not evaluable. The time to progression was 6 months for the patient with partial response, and 2, 5.5+ and 11 months for three patients with stable disease. The estimated median overall survival was 4.7 months (confidence interval, 2.2-9.9 months; range, 0.9-31.5 months), and median progression-free survival was 1.8 months (confidence interval, 1.5-3.0 months; range, 0.5-14 months). Grade 3 toxicities related to treatment included neutropenia (n=5), elevation of transaminases (n=2), and neuropathy (n=1). No treatment-related deaths were experienced. Thalidomide+IFN is a safe and tolerable palliative treatment for previously treated stage IV melanoma.
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PMID:A pilot study of low-dose thalidomide and interferon alpha-2b in patients with metastatic melanoma who failed prior treatment. 1762 52

Bevacizumab, an anti-vascular endothelial growth factor recombinant humanized monoclonal antibody, directly inhibits tumor angiogenesis and hence tumor growth. First-line therapy with intravenous bevacizumab 10 mg/kg every 2 weeks plus subcutaneous interferon-alpha-2a 9 million international units three times weekly has been evaluated in two randomized, double-blind or open-label, multicenter phase III trials (AVOREN [n = 649] and CALGB 90206 [n = 732]). Bevacizumab combination therapy resulted in a median progression-free survival that was significantly (p < or = 0.0001) longer than that seen with placebo plus interferon-[alpha]-2a in AVOREN (10.2 vs 5.4 months) [hazard ratio (HR) 0.63 (95% CI 0.52, 0.75)] and that seen with interferon-alpha-2a alone in CALGB 90206 (8.5 vs 5.2 months). Overall survival data in AVOREN and CALGB 90206 are not yet mature. In the interim overall survival analysis in AVOREN, median overall survival was 19.8 months with placebo plus interferon-alpha-2a, but had not yet been reached with bevacizumab plus interferon-alpha-2a (HR 0.79 [95% CI 0.62, 1.02; p = 0.0670]). The overall tumor response rate with bevacizumab plus interferon-alpha-2a was significantly (p < or = 0.0001) higher than with placebo plus interferon-alpha-2a in AVOREN (31% vs 13%) and that with interferon-alpha-2a alone in CALGB 90206 (25.5% vs 13.1%). Subgroup analyses in AVOREN suggested that interferon-alpha-2a dose reductions (to manage grade > or =3 adverse events attributable to the drug) did not compromise the efficacy of combination treatment with bevacizumab plus interferon-alpha-2a. The addition of bevacizumab to interferon-alpha-2a in AVOREN was generally well tolerated. No unexpected/new adverse events were observed; bevacizumab-associated toxicities were generally of mild intensity.
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PMID:Bevacizumab: in first-line treatment of advanced and/or metastatic renal cell carcinoma. 1834 8


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