Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q16637 (SMA)
 8,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The long-acting synthetic somatostatin analog, SMA 201-995, was used to treat patients with advanced hormonal-refractory prostate cancer. Twenty-two of 24 study patients treated are evaluable for toxicity and 20 are evaluable for response. The dose of SMS 201-995 was 100 mg subcutaneously every 8 hours for 6 weeks. Two patients suffered intolerable gastrointestinal complications requiring early cessation of therapy. No patient had objective evidence of tumor regression. After developing a clinical suspicion that tumor growth accelerated with SMS 201-995, we observed 10 patients closely for 2 months before beginning SMS 201-995 treatment and for the first 2 months on the therapy. In these 10 patients, the serum prostatic acid phosphatase level rose at an accelerated rate after 1 to 2 months of treatment. Among the 20 patients treated and evaluable for response, new osseous metastases developed in 12 and new visceral metastases in 4; 1 developed disseminated intravascular coagulation and 2 developed neurologic complications (mean time to objective progression, 5.6 weeks). Six patients received salvage chemotherapy after disease progressed on SMS 201-995 therapy, 5 of whom have achieved objective tumor regressions. We believe SMS 201995 stimulates prostatic tumor growth and may sensitize tumor cells to subsequent chemotherapy.
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PMID:SMS 201-995 in the treatment of refractory prostatic carcinoma. 787 9

It has been hypothesized that transforming growth factor beta (TGF-beta) may prevent immune-mediated glioma cell elimination; however, previous work has also indicated that increased TGF-beta may lead to reduced proliferation, induction of apoptosis, and enhancement of Fas-induced apoptosis. We have investigated the role of TGF-beta in the progression of malignant glioma using an immunocompetent murine model. SMA 560 malignant glioma cells were stably transfected with constructs that resulted in over- or underproduction of active TGF-beta1. Using these cell lines, we have shown that (a) TGF-beta1 inhibits induction of antitumor cytotoxicity when the tumor cells are given s.c. but not when they are given intracranially; (b) Fas/APO-1 is expressed on SMA 560 cells in vitro and in vivo, SMA 560 cells are susceptible to TGF-beta1- and Fas-induced apoptosis in vitro, and TGF-beta1 and Fas act synergistically to induce glioma cell death; (c) increased levels of endogenous TGF-beta1 production by SMA 560 cells lead to increased sensitivity to Fas-mediated apoptosis; (d) overproduction of endogenous TGF-beta1 reduces the rate of s.c. SMA 560 tumor growth and also reduces the tumorigenicity of tumors located in the central nervous system, with opposite effects observed with underproduction of TGF-beta1 using antisense cell lines; and (e) the observed changes in growth parameters in vivo were associated with increased rates of apoptosis in TGF-beta1-overproducing cells. Taken together, these results indicate that, despite decreased induction of CTL responses, the dominant net effect of TGF-beta1 on the growth of the SMA 560 murine high-grade glioma in vivo is growth inhibition. This contrasts with results seen with non-central nervous system malignant tumors in immunocompetent animals, in which TGF-beta1 production provides a major growth advantage.
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PMID:Endogenous expression of transforming growth factor beta1 inhibits growth and tumorigenicity and enhances Fas-mediated apoptosis in a murine high-grade glioma model. 944 9

We have previously reported that local secretion of either TNF-alpha or TGF beta1 by intracerebral SMA-560 malignant glioma tumor cells can reduce or eliminate tumor growth in mice. However, the use of TNF-alpha, while improving the overall survival of tumor bearing animals, was associated with early toxic deaths due to cerebral edema. In the present study, we demonstrate that TNF-alpha induces apoptosis of the SMA 560 cell line, as does TGF beta1, and that these two cytokines act in an additive fashion to enhance apoptosis and thus, to inhibit SMA 560 cell growth in vitro. Next, we show that the production of TGF beta1 when added to TNF-alpha production by central nervous system tumors in vivo abrogates any early deaths seen due to TNF-alpha toxicity and leads to a larger percentage of animals surviving CNS tumor challenge. Finally, we demonstrate that the production of TGF beta1 by tumor cells is associated with the abolition of tumor-associated cerebral edema in both TNF-alpha and in non-TNF-alpha producing tumors. These results are important for the development of effective and less toxic therapies for brain tumors, as well as for examining the pathogenesis of tumor-related cerebral edema.
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PMID:Local production of TGF beta1 inhibits cerebral edema, enhances TNF-alpha induced apoptosis and improves survival in a murine glioma model. 965 71

MLS ovarian epithelial carcinoma multicellular spheroids xenografted subcutaneously in CD-1 nude mice displayed growth delay, or dormancy, of up to 52 days. In the study reported here, implanted MLS spheroids were used for testing the role of angiogenesis and vascular maturation in triggering the initiation of tumor progression. The kinetics and impact of neovascular maturation and functionality, in dormancy, and growth of MLS spheroid xenografts were studied noninvasively by BOLD contrast MRI. MR data were supported by histologic staining for biotinylated albumin as a blood pool marker and alpha-smooth muscle actin (alpha-SMA) as marker for perivascular mural cells. Although the tumor periphery showed higher levels of total and mature vasculature than normal skin, the fraction of mature out of the total vessels as detected by MRI vascular maturation index (VMI(MRI)) was significantly lower in the tumor both before and after tumor exit from dormancy. The neovasculature induced by the implanted spheroid was unstable and showed cycles of vessel growth and regression. Surprisingly, this instability was not restricted to the immature vessels, but rather included also regression of mature vessels. During dormancy, neovasculature was predominantly peripheral with no infiltration into the implanted spheroid. Infiltration of alpha-SMA positive stroma cells into the spheroid was associated with functional vascularization and tumor growth. Thus, stroma infiltration and vascular maturation are an important checkpoint linking the angiogenic switch with initiation of tumor progression.
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PMID:The role of angiogenesis, vascular maturation, regression and stroma infiltration in dormancy and growth of implanted MLS ovarian carcinoma spheroids. 1469 16

The two-kringle domain of tissue-type plasminogen activator (t-PA) has previously been shown to contain anti-angiogenesis activity. In this study, we explored the potential in vivo anti-tumor effects of the recombinant kringle domain (TK1-2) of human t-PA. Anti-tumor effects of purified Pichia-driven TK1-2 were examined in nude mice models by subcutaneous implantation of human lung (A-549) and colon (DLD-1, HCT-116) cancer cell lines. Mice bearing the tumors were injected with PBS or purified TK1-2 (30 mg/kg) i.p. every day for 22 days. TK1-2 treatment suppressed the A-549, DLD-1, and HCT-116 tumor growth by 85.3%, 52.4%, and 62.5%, respectively. Immunohistological examination of the tumor tissues showed that TK1-2 treatment decreased the vessel density and also the expression of angiogenesis-related factors including angiogenin, VEGF, alpha-SMA, vWF, and TNF-alpha, and increased the apoptotic fraction of cells. TK1-2 neither inhibited in vitro growth of these cancer cells nor affected t-PA-mediated fibrin clot lysis. These results suggest that TK1-2 inhibits the tumor growth by suppression of angiogenesis without interfering with fibrinolysis.
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PMID:The kringle domain of tissue-type plasminogen activator inhibits in vivo tumor growth. 1565 16

The two-kringle domain of tissue-type plasminogen activator (TK1-2) has been identified as a novel angiogenesis inhibitor. In the previous study, purified Pichia-derived TK1-2 has been shown to suppress in vivo growth of human lung and colon cancer cells. Here, we demonstrate that E. coli-derived non-glycosylated TK1-2 suppresses tumor growth more potently than Pichia-derived TK1-2 and prolongs the survival of tumor bearing mice. The recombinant TK1-2 prepared through E. coli expression, His-tag affinity chromatography and in vitro refolding was injected intraperitoneally once daily into nude mice 7 days after subcutaneous implantation with PC14 lung cancer cells (n=10). Measurement of tumor volumes indicated that low-dose TK1-2 treatment (10 mg/kg) suppressed tumor growth by approximately 85.2% (p<0.01), while high-dose TK1-2 treatment (50 mg/kg) even more potently inhibited tumor growth (>93.8%) (p<0.005). Treatment of TK1-2 also prolonged the survival of tumor-bearing mice in a dose-dependent fashion. In an independent HCT116 xenograft model, E. coli-derived TK1-2 was more effective in suppressing tumor growth than Pichia-derived TK1-2. Immunohistochemical analysis of tumor tissue also revealed that the expression of VEGF, SMA-alpha, TNF-alpha and angiogenin was less positive in the E. coli-derived TK1-2-treated group than in the Pichia-derived TK1-2-treated group. These results suggest that E. coli-derived refolded, non-glycosylated TK1-2 can be used more effectively as an anti-cancer agent.
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PMID:Potent anti-tumor and prolonged survival effects of E. coli-derived non-glycosylated kringle domain of tissue-type plasminogen activator. 1639 90

Angiogenesis is essential for tumor growth, invasion, and metastatic spread. Whereas microvessel density (MVD) has been widely used as a measure of tumor-associated angiogenesis, we now wanted to examine the significance of other angiogenic markers, especially vascular proliferation (by Ki-67/factor VIII staining) and the degree of pericyte coverage [by alpha-smooth muscle actin (alpha-SMA)/factor VIII staining], in a large and population-based series of endometrial carcinoma with complete follow-up. Due to limited information on the role of lymphangiogenesis in these tumors, lymphatic vessel density (LVD) by LYVE-1 staining was also determined, as well as selected angiogenic factors [vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D and basic fibroblast growth factor (bFGF)], which could possibly be related to vascular proliferation and lymphangiogenesis. The information on angiogenic phenotype was related to clinicopathologic features and disease progress. Median vascular proliferation, as estimated by vascular proliferation index (VPI), was 3.9% and high VPI was associated with features of aggressive tumors and decreased survival. The prognostic effect of VPI was superior to that of MVD. Presence of pericyte coverage, as estimated by the alpha-SMA index (SMAI), was 35% and low SMAI was significantly associated with vascular invasion by tumor cells and impaired prognosis. Peritumoral lymphatic vessels (LVD-pt) were found in 39.5% of the cases and high LVD-pt was significantly associated with aggressive tumor features and decreased survival. In multivariate survival analysis, only the extent of vascular proliferation had independent prognostic effect, in addition to well-known clinicopathologic factors, whereas MVD did not have significant prognostic value. In conclusion, our study indicates that vascular proliferation is a meaningful variable in assessing the angiogenic phenotype of endometrial carcinoma.
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PMID:Vascular proliferation is important for clinical progress of endometrial cancer. 1654 Jun 84

Zn-protoporphyrin (ZnPP) is a promising candidate for cancer therapy. It is known to inhibit heme-oxygenase-1 (HO-1), resulting in suppressed biliverdin/bilirubin production accompanying lowered antioxidative capacity. As a consequence, a significant suppression of tumor growth in vivo was reported. Recent findings also showed that ZnPP efficiently generated reactive singlet oxygen under illumination of visible light. In the present report, we describe the photosensitizing capabilities of water-soluble polymer conjugates of ZnPP as novel compounds for photodynamic therapy against solid tumors. The polymer conjugation made ZnPP water-soluble, thus possible for injection for its aqueous solution. The cellular uptake and photobiological activity of ZnPP derivatives have been tested using a human T-cell leukemia cell line in vitro and demonstrated most potent phototoxic effects of SMA-ZnPP followed by PEG-ZnPP under aerobic conditions.
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PMID:Water-soluble polymer conjugates of ZnPP for photodynamic tumor therapy. 1727 24

We have previously reported that inducible overexpression of the serine protease inhibitor nexin 2 (SERPINE2) significantly increases local invasiveness of subclones of the pancreatic cancer cell-line SUIT-2 in nude mouse xenografts. This was associated with a striking increase of extracellular matrix deposition in the invasive tumors. Pancreatic stellate cells (PSCs) have recently been identified as the major source of fibrosis in pancreatic adenocarcinomas. Here we report that co-injection of PSCs and tumor cells dramatically enhances the invasive potential of serine protease inhibitor Nexin 2 (SERPINE2)-expressing SUIT-2 cells. 100% (24 of 24) of the SERPINE2-expressing tumors with PSCs grew aggressively invasive, as compared to 39% of SERPINE2-negative tumors with PSCs and 27% of SERPINE2-expressing tumors without PSCs. In contrast to pure cancer cell preparations, SERPINE2 overexpression in the presence of PSCs also resulted in increased tumor growth. Histological evaluation demonstrated the presence of large amounts of ECM deposits co-localizing with cells staining positive for the PSC marker alpha-SMA. We conclude that PSCs actively proliferate in pancreatic cancer xenograft tumors and significantly contribute to the local invasive potential of the tumors. Presence of PSCs enhances the pro-invasive effects of SERPINE2 expression, and SERPINE2 influences tumor growth (as opposed to invasiveness) only in the presence of PSCs. Our data thus suggest that SERPINE2 is an important modulator of tumor cell/host interactions in pancreatic cancer.
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PMID:Pancreatic stellate cells potentiate proinvasive effects of SERPINE2 expression in pancreatic cancer xenograft tumors. 1770 87

Activated fibroblasts are associated with many different tumors. Myofibroblasts, activated fibroblasts, and perivascular mesenchymal cells such as pericytes play a role in cancer progression. Many studies suggest that myofibroblasts facilitate tumor growth and cancer progression. The source for myofibroblasts and other activated fibroblasts within the tumors is still debated. Although de novo activation of quiescent fibroblasts into alpha-smooth muscle actin (alpha SMA)-positive myofibroblasts is one likely source, epithelial to mesenchymal transition and bone marrow recruitment are also evolving as possible mechanisms for the emergence of a heterogeneous population of carcinoma-associated fibroblasts. Here, we show that transforming growth factor-beta1 could induce proliferating endothelial cells to undergo a phenotypic conversion into fibroblast-like cells. Such endothelial to mesenchymal transition (EndMT) is associated with the emergence of mesenchymal marker fibroblast-specific protein-1 (FSP1) and down-regulation of CD31/PECAM. Additionally, we show EndMT in tumors using the B16F10 melanoma model and the Rip-Tag2 spontaneous pancreatic carcinoma model. Crossing Tie2-Cre mice with R26Rosa-lox-Stop-lox-LacZ mice allows for irreversible tagging of endothelial cells. We provide unequivocal evidence for EndMT at the invasive front of the tumors in these transgenic mice. Collectively, our results show that EndMT is a unique mechanism for the accumulation of carcinoma-associated fibroblasts and suggest that antiangiogenic treatment of tumors may have a direct effect in decreasing activated fibroblasts that likely facilitate cancer progression.
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PMID:Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. 1797 53


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