Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P08758 (annexin V)
9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vector-mediated transfer of prodrug-activating genes provides a promising means of cancer gene therapy. In a search for more selective and more potent bioactivating enzymes for gene therapy of malignant brain tumors, the toxicity-generating capacity of the rabbit cytochrome P450 isozyme CYP4B1 was investigated. Rabbit CYP4B1, but not rat or human isozymes, efficiently converts the inert prodrugs, 2-aminoanthracene (2-AA) and 4-ipomeanol (4-IM), into highly toxic alkylating metabolites. Toxicity of these two prodrugs was evaluated in culture in parental and genetically modified rodent (9L) and human (U87) glioma cell lines stably expressing CYP4B1, and in vivo in a subcutaneous 9L tumor model in nude mice. The most sensitive CYP4B1-expressing glioma clone, 9L4B1-60, displayed an LD50 of 2.5 microM for 2-AA and 4-IM after 48 h of prodrug incubation, whereas 20 times higher prodrug concentrations did not cause any significant toxicity to control cells. Substantial killing of control tumor cells by 2-AA was achieved by co-culturing these cells with CYP4B1-expressing cells at a ratio of 100:1, and toxic metabolites could be transferred through medium. In both CYP4B1-expressing cells and co-cultured control cells, prodrug bioactivation was associated with DNA fragmentation, as assayed by fluorescent TUNEL assays and by annexin V staining. Alkaline elution of cellular DNA after exposure to 4-IM revealed extensive protein-DNA crosslinking with single-strand breakage. Growth of 9L-4B1 tumors in nude mice was inhibited by intraperitoneal injection of 4-IM with minimal side effects. Potential advantages of the CYP4B1 gene therapy paradigm include: the low concentrations of prodrug needed to kill sensitized tumor cells; low prodrug conversion by human isozymes, thus reducing toxicity to normal cells; a tumor-killing bystander effect that can occur even without cell-to-cell contact; and the utilization of lipophilic prodrugs that can penetrate the blood-brain barrier.
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PMID:New prodrug activation gene therapy for cancer using cytochrome P450 4B1 and 2-aminoanthracene/4-ipomeanol. 965 Jun 11

Chemoprevention of colorectal cancer using aspirin has been demonstrated in rodents and has been suggested by data from epidemiological studies. The mechanism that accounts for this prevention is unknown, but it is thought to relate to an irreversible inhibition of cyclooxygenase and, subsequently, prostaglandin production. The effect of aspirin on the growth of human colonic tumor cells was determined in an effort to gain insight into a possible mechanism of action. In the two cell lines studied, SW 620 and HT-29, we observed a significant dose- and time-dependent increase in aspirin toxicity in a concentration range of 1.25-10 mM. This result was independent of prostaglandin production, because there was no measurable prostaglandin E2 in cell culture medium. As compared with controls, cells in cultures that contained aspirin were not detached, which suggests that the mechanism of cell death was not apoptosis. Flow cytometric analysis revealed an increase in S phase and G2-M populations as well as the number of subdiploid nuclei in cultures treated with high-dose aspirin. Confirmation that cells were undergoing necrosis in response to aspirin was evident from the presence of cells that bound annexin V and accumulated propidium iodide in the absence of a population that bound annexin alone. The results suggest that aspirin induces cell cycle arrest and causes necrosis at high concentrations in vitro, but does not induce apoptosis. Collectively, these two events, necrosis and cell cycle arrest, may contribute to the chemopreventive effect that seems to result from long-term administration of aspirin in vivo.
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PMID:Aspirin toxicity for human colonic tumor cells results from necrosis and is accompanied by cell cycle arrest. 966 90

Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesions. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to induce apoptosis in a variety of tumor cell lines. To evaluate whether these agents also induce apoptosis of VSMCs, cultured rat VSMCs were treated with increasing doses of atorvastatin in the presence of FBS as a survival factor. The presence of apoptosis was evaluated by morphological criteria, annexin V binding, and DNA fragmentation and quantified as the proportion of hypodiploid cells by flow cytometry. Atorvastatin induced apoptosis in a dose-dependent manner, an effect also seen with simvastatin and lovastatin, but not with the hydrophilic drug pravastatin. The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterols was >95% and was fully reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate but not by isopentenyl adenosine, ubiquinone, or squalene, suggesting a role for prenylated proteins in the regulation of VSMC apoptosis. To further assess the role of protein prenylation, VSMCs were exposed to the prenyl transferase inhibitors perillic acid and manumycin A. Both agents induced VSMC apoptosis as evaluated by the above-mentioned criteria. Finally, VSMC treatment with lipophilic statins was associated with decreased prenylation of p21-Rho B, further supporting the role of protein prenylation inhibition in statin-induced VSMC apoptosis. The present data suggest that interference with protein prenylation by HMG-CoA reductase inhibitors or other agents may provide new strategies for the prevention of neointimal thickening.
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PMID:3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. 973 71

The antiangiogenic, tubulin-binding drug combretastatin A-4 exhibits a selective toxicity for proliferating endothelial cells in vitro and induces vascular shutdown in tumor models in vivo. The mechanism of combretastatin A-4 cytotoxicity has now been investigated with cultured proliferating human umbilical vein endothelial cells by examining various markers of apoptosis. Incubation of cells with 0.1 mM combretastatin A-4 induced the conversion (first detected after 6 h) of the CPP32 proenzyme to active caspase-3, a cysteine protease that plays an important role in apoptosis in many cell types; the drug also increased caspase-3 activity. Another early event observed was the binding of annexin V to 50% of the cells 8 h after drug treatment. Internucleosomal DNA fragmentation, another hallmark of apoptosis, was detected in cells incubated with 0.1 mM combretastatin A-4 for 24 h. Staining with Hoechst 33258 revealed that about 75% of cells exhibited a nuclear morphology characteristic of apoptosis after incubation with drug for 24 h. Incubation of cells for up to 8 h with combretastatin A-4 did not induce the release of lactate dehydrogenase or increase the uptake of propidium iodide, both indicators of membrane integrity. These results indicate that the selective cytotoxic effect of combretastatin A-4 is mediated by the induction of apoptosis rather than by necrosis and may provide an enhanced clinical strategy in cancer chemotherapy with this new agent.
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PMID:Induction of apoptosis in proliferating human endothelial cells by the tumor-specific antiangiogenesis agent combretastatin A-4. 978 91

Tissue factor (TF), the membrane glycoprotein that initiates blood coagulation, is constitutively expressed by many tumor cells and is implicated in peri-tumor fibrin deposition and hypercoagulability in cancer. Upregulation of tumor TF correlates with enhanced metastatic potential. Furthermore, TF has been colocalized with VEGF in breast cancer, specially at sites of early angiogenesis. There are no data on the effect of hypoxia on tumor cell TF expression. Since hypoxia is known to stimulate VEGF production, we studied whether this also induces tumor cell TF expression. Confluent monolayers of A375 melanoma, MCF-7 breast carcinoma and A549 lung carcinoma were cultured in either 95% air, 5% CO2 (normoxic) or 95% N2, 5% CO2 (hypoxic; 25-30 mmHg) for 24 h. Procoagulant activity (PCA) was measured by amidolytic and clotting assays, surface TF antigen by flow cytometry, early apoptosis by annexin V binding and VEGF levels in culture supernatants by ELISA. Hypoxia significantly increased tumor cell PCA in all three cell lines tested and TF antigen on A375 cells was increased four-fold (P <0.05). Pentoxifylline (PTX), a methylxanthine derivative, significantly inhibited the hypoxia-induced increase in PCA as well as VEGF release in all three cell lines tested. In A375 cells, PTX significantly inhibited TF antigen expression by both normoxic and hypoxic cells. Hypoxia induced a slight (5%) but not significant, increase in early apoptosis. Intravenous injection of hypoxic A375 cells into nude rats produced more pronounced thrombocytopenia (n = 5, P <0.01) and more lung metastases (n = 3, P <0.05) compared to normoxic cells. We conclude that hypoxia increases TF expression by malignant cells which enhances tumor cell-platelet binding and hematogenous metastasis. Hypoxia-induced upregulation of TF appears to parallel that of VEGF, although the mechanism remains unclear.
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PMID:Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor. 979 77

A breast tumor hypoxia model used to simulate conditions which may exist within an enlarging tumor was examined using documented methods for identifying mechanisms of cell death and compared to the mitochondrial membrane-specific APO2.7 antigen expression. Hypoxic conditions were induced by holding cell pellets of MDA-MB-175-VII breast carcinoma cells in tightly capped centrifuge tubes for up to 10 days. Cells were harvested at 1.5, 3, 4.5, 6, 12, 18, and 24 h, and each 24 h thereafter to 10 days. APO2.7 was monitored in unprocessed cells (no permeabilization prior to staining) for all time points and processed cells (permeabilized prior to staining) for only the first 24 h. Cell viability probes trypan blue and anti-tubulin antibody showed a rapid increase in staining over the first 24 h, as did the phosphatidylserine-specific annexin V and DNA fragmentation by flow cytometry (range of 60-81% positive staining). Light scatter changes indicative of cell death were also quite remarkable. APO2.7 staining never exceeded 42% of the cell pellet over the 10 days of testing compared to greater than 95% staining for all other methods tested. When APO2.7 antigen expression was examined with respect to depth in the cell pellet, it was apparent that cells deeper in the pellet expressed APO2.7 more rapidly; however, fewer cells stained and cells showed fewer apoptotic features on an ultrastructural level than cells at the cell media interface. The study indicates that the anti-APO2.7 antibody may be able to discern apoptotic and incomplete apoptotic cells from necrotic MDA-MB breast cancer cells, traversing a heterogeneous pathway to cell death induced by hypoxia.
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PMID:APO2.7 defines a shared apoptotic-necrotic pathway in a breast tumor hypoxia model. 982 43

Several lines of evidence now indicate that type 1 insulin-like growth factor receptor (IGF1R) function may be particularly important in the pathogenesis of the pediatric cancer neuroblastoma. Modulating the expression of specific genes involved in neuroblastoma tumorigenesis could provide a much needed alternative treatment strategy for poor prognosis disease. We now report construction of an antisense expression vector to the IGF1R that markedly reduces cellular IGF1R levels and inhibits the proliferation and clonogenicity of neuroblastoma cells in vitro but not that of IGF1R null cells. This antitumor activity is associated with the induction of apoptotic cell death in transfected cells, as measured by annexin V staining and flow cytometry. Direct injection of this vector into established tumors growing in syngeneic mice results in a marked inhibition of tumor growth with complete and durable tumor regression in one-half of the animals. This effect appears to be immunologically mediated in that vector injection of neuroblastoma tumors growing in severe combined immunodeficiency mice results in only modest delay of tumor growth. Our results suggest that inhibition of IGF1R expression by direct intratumoral delivery of an antisense construct could provide a novel therapeutic approach in the management of poor prognosis neuroblastoma.
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PMID:Inhibition of insulin-like growth factor I receptor expression in neuroblastoma cells induces the regression of established tumors in mice. 985 76

Immunologic escape includes the loss of Fas-receptor and the gain of Fas-ligand expression. Normal adrenal glands express the Fas-receptor and MHC class II molecules in inner cortical zones. A distinctive feature of adrenocortical tumors is the loss of MHC class II expression. Here we demonstrate loss of Fas and gain of Fas-ligand expression in the adrenocortical carcinoma cell line NCI-H295 by immunohistochemistry and RT-PCR. In a co-culture system of tumor cells and HLA-matched leukocytes, CD 8-positive or CD 4-positive lymphocytes, we examined the immunologic escape and the ability to induce apoptosis in the immune cells. The direct co-culture with either leukocytes, CD 8-positive or CD 4-positive lymphocytes reduced spontaneous apoptosis in immune cells from 49.9% to 13.0%, 8.6% and 15.3%, respectively, as determined by FACS analysis of Annexin V binding and LDH release in the medium. In co-culture, cortisol secretion increased up to 200%. Cellular communication does not induce apoptosis in immune cells, but promotes their survival. This may be due to partial HLA class I mismatches contributing to immunologic activity. The viability of the tumor cells was not affected, and these cells were stimulated to secrete cortisol. In summary, immune escape of adrenocortical carcinomas may occur because of altered Fas/Fas-L system expression and loss of MHC class H expression.
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PMID:The mercy of adrenocortical tumor cells on lymphocytes. 988 63

Calcium-binding proteins may endow tumor cells with properties related to their malignancy and metastatic phenotype. Chromatographic procedures and amino acid sequence analysis were used in this study to identify seven calcium-binding proteins, annexin VI, cap g, annexin V, calmodulin, S100A11, S100B and S100A6, associated with uveal melanoma, the primary ocular tumor of adults. This series of calcium-binding proteins was identified in both primary tumors and cell lines of uveal melanoma. Several of the proteins were shown by immunochemical methods to be differentially expressed between normal uveal melanocytes and malignant melanomas of the uvea. In addition, the expression of S100A6 may correlate with the malignant properties of the tumor.
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PMID:The identification and differential expression of calcium-binding proteins associated with ocular melanoma. 992 Apr 19

In order to improve the therapeutic efficacy of adoptive immunotherapy of cancer using IL-2-activated NK (A-NK) cells, we developed a bi-specific monoclonal antibody (BimAb) 3.2.3xCC52. One specificity of the BimAb (mAb 3.2.3) was directed against rat CD161A (NKR-P1A) which has been shown to be an activation structure on rat NK cells involved in lysis of target cells and cytokine secretion. The other specificity (mAb CC52) was directed against a tumor associated antigen on the rat colon adenocarcinoma cell line CC531. The hybridomas producing 3.2.3 and CC52 were fused, resulting in a quadroma producing the desired 3.2.3xCC52 BimAb. The hybridomas produced antibodies of different isotypes (IgG2b and IgG1 respectively) which enabled us to pre-select quadromas with a high likelihood for production of BimAb, through testing for the production of bi-isotypic antibodies. Production of functional BimAb by the selected quadromas was demonstrated in an assay showing enhanced conjugate formation between CD161A+ cells and CC531 tumor cells. We also tested the 3.2.3xCC52 BimAb for its capacity to enhance NK cell-mediated lysis of CC531 tumor cells in 4 h and 19 h 51Cr release assays; in a prolonged (2 day) tumor neutralization assay using a tetrazolium salt (MTT)-based assay; and in tests for apoptosis using Annexin V-FITC. Although this BimAb was not demonstrated to cause enhanced lysis of CC531 cells by CD161A+ effector cells in vitro, it might be a useful tool to enhance the number of NK cells at the tumor site and/or prolong contact between tumor cells and NK cells in vivo, thereby probably enhancing the therapeutic efficacy of NK cells.
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PMID:The development of a bi-specific anti-CD161A x anti-tumor antibody for rat NK cell targeting. 1008 94


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