Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated plasma concentrations of endogenous thrombin generation markers and thrombotic events have been reported in children with leukemia. The aim of this study was to evaluate the effects of cancer and its treatment on thrombin generation (TAT levels) in children with acute lymphoblastic leukemia (ALL). The authors evaluated 32 children (23 M, 9 F) aged between 1 and 15 years (mean 6) affected by ALL (immunophenotypic subgroups: 16 common, 7 T, and 9 pre-B type). In all patients TAT levels at onset and after 5-6 doses of L-asparaginase were evaluated. TAT levels were higher in patients both at onset (13.04 +/- 10.90 ng/L) and after the 5-6 doses of L-asp (19.41 +/- 11.05 ng/L) with respect to controls (4 +/- 1 ng/L) (p < .001 and p < .001). TAT levels after 5-6 doses of L-asp were higher than those at onset (p < .001). Factorial ANOVA showed that at onset there was a significant effect of leukemia immunophenotypic subgroups upon TAT levels (p < .05) and no effect of inherited thrombotic risk factors. These results indicate that in children with ALL an important role is played by acquired thrombotic risk factors, among which the indirect cancer procoagulant activity has its importance.
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PMID:Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia immunophenotypic subgroups. 1112 98

The protein transduction domain (PTD) embedded in the HIV TAT protein (amino acids 47-57) has been shown to successfully mediate the introduction of heterologous peptides and proteins in excess of Mr 100,000 into mammalian cells in vitro and in vivo. We report here that the modeled structure of the TAT PTD is a strong amphipathic helix. On the basis of this information, we synthesized a series of synthetic PTDs that strengthen the alpha-helical content and optimize the placement of arginine residues. Several PTD peptides possessed significantly enhanced protein transduction potential compared with TAT in vitro and in vivo. These optimized PTDs have the potential to deliver both existing and novel anticancer therapeutics.
Cancer Res 2001 Jan 15
PMID:Synthetic protein transduction domains: enhanced transduction potential in vitro and in vivo. 1121 34

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in patients with VHL disease and in the majority of patients with sporadic renal cell carcinomas (RCCs). RCCs are dependent on insulin-like growth factor-1 receptor-mediated signaling for tumor growth and invasion in vivo. Reintroduction of the VHL gene product (pVHL) can inhibit on insulin-like growth factor-I receptor-mediated signaling in RCC cells in vitro through interaction with protein kinase C delta and is mediated by a specific amino acid sequence (104-123) in the beta-domain of the pVHL. In the present study, the amino acid sequence (104-123) of the pVHL was conjugated to the protein transduction domain of HIV-TAT protein (TATFLAGVHL-peptide) to facilitate entry into cells, and we demonstrate that this amino acid region of VHL is sufficient to block proliferation and invasion of 786-O renal cancer cells in vitro. Furthermore, daily i.p. injections with the TATFLAGVHL peptide retarded and, in some cases, caused partial regression of renal tumors that were implanted in the dorsal flank of nude mice. Treatment with this peptide also inhibits the invasiveness of renal tumors. A 56% decrease in the proliferative index in tumors treated with the TATFLAGVHL-peptide versus control-peptide-treated mice was observed. Taken together, these results show the novel importance of a 20-amino acid sequence of the beta-domain of the VHL gene product capable of inhibiting tumor growth and invasion. These results lay the foundation for a unique approach toward treating RCCs using this small-molecular-weight peptide fused to the TAT-sequence, which may, in the future, be used alone or in conjunction with other therapies.
Cancer Res 2001 Mar 01
PMID:The 104-123 amino acid sequence of the beta-domain of von Hippel-Lindau gene product is sufficient to inhibit renal tumor growth and invasion. 1128 Jul 20

Gain-of-function mutation in c-kit proto-oncogene exon 11 has been described in about 20 -- 50% of gastrointestinal stroma tumor (GIST). Recently, additional mutational hot-spots in exon 9 and exon 13 of the c-kit gene have been reported in GISTs without mutations of exon 11, but a subsequent report in a Western population indicated that only a small portion of GISTs (eight of 200 GISTs, 4%) showed mutations in these regions. In this study, we evaluated mutations in exon 9 and exon 13 of the c-kit gene by both polymerase chain reaction-single strand conformation polymorphism analysis and direct sequencing in 48 GISTs in a Japanese population, for which the clinicopathological and immunohistochemical features and mutations in exon 11 had previously been reported. C-kit gene mutation in exon 9, representing insertion of GCC TAT, was identified in only 4 of 48 GISTs (8%), and none of the GISTs had mutations in exon 13. All four GISTs with mutation in exon 9 were high-risk, and the patients died of multiple tumor metastasis. Mutations in exon 9 and exon 13 of the c-kit gene were also rare events in Japanese GISTs and were related to a poor prognosis. These results in Japanese are consistent with those in Western populations, although a preferential occurrence of GISTs with exon 9 mutation in the small intestine, which was suggested in a previous report, was not observed.
Jpn J Cancer Res 2001 May
PMID:Mutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese. 1137 57

Cancer patients are subjected to increased systemic risk of thrombotic events and may therefore be at higher risk of even local thrombosis compromising the outcome of reconstructive microsurgery. Coagulation and fibrinolysis activities were studied serially during and after reconstructive microsurgery in seven patients with oropharyngeal cancer or sarcoma in the extremities. A preoperative hypercoagulable state was found in four patients (elevated fibrinogen, TAT, F1+2, or D-dimer); two of these patients also had a local thrombotic event. In all patients, the plasma markers generally varied perioperatively: fibrinogen decreased, whereas TAT and subsequently D-dimer increased at the end of the operation. However, tPA and PAI-1 remained unaltered, except in the patients with thrombosis in whom PAI-1 activity increased progressively during the operation. F1+2 was also clearly elevated in these two patients at the time of thrombosis. Preoperative assessment of hypercoagulability for this group of patients could be helpful in targeting meticulous antithrombotic protection.
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PMID:Activation of coagulation and fibrinolysis during reconstructive microsurgery in patients with cancer. 1149 94

Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than normal tissues. These impart resistance to radiotherapy and anticancer chemotherapy, as well as predisposing to increased tumor metastases. To develop a potentially therapeutic protein drug highly specific for solid tumors, we constructed fusion proteins selectively stabilized in hypoxic tumor cells. A model fusion protein, oxygen-dependent degradation (ODD)-beta-galactosidase (beta-Gal), composed of a part of the ODD domain of hypoxia-inducible factor-1alpha fused to beta-Gal, showed increased stability in cultured cells under a hypoxia-mimic condition. When ODD-beta-Gal was further fused to the HIV-TAT protein transduction domain (TAT(47-57)) and i.p. injected to a tumor-bearing mouse, the biologically active fusion protein was specifically stabilized in solid tumors but was hardly detected in the normal tissue. Furthermore, when wild-type (WT) caspase-3 (Casp3(WT)) or its catalytically inactive mutant was fused to TAT-ODD and i.p. injected to a tumor-bearing mouse, the size of tumors was reduced by the administration of TAT-ODD-Casp3(WT) but not by TAT-ODD-mutant Casp3. TAT-ODD-Casp3(WT) did not cause any obvious side effects on tumor-bearing mice, suggesting specific stabilization and activation of the fusion protein in the hypoxic tumor cells. These results suggest that the combination of protein therapy using a cytotoxic TAT-ODD fusion protein with radiotherapy and chemotherapy may provide a new strategy for annihilating solid tumors.
Cancer Res 2002 Apr 01
PMID:Antitumor effect of TAT-oxygen-dependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells. 1192 18

To evaluate whether all-trans-retinoic acid (ATRA) is able to modulate the hemostatic system in patients with solid tumors, we studied patients with locally advanced breast cancer who were enrolled in a Phase Ib study of ATRA +/- Tamoxifen (Tam). In this study, two groups of 15 patients/each were treated for 21 days before operation with ATRA at three doses (15, 45, or 75 mg/m(2)/day on alternate days) given alone (group 1) or in combination with Tam (group 2). One additional group received Tam alone. Plasma samples were evaluated for hypercoagulation markers (FVIIa, F1+2, TAT, D-dimer), fibrinolysis proteins (t-PA, PAI-1), and coagulation inhibitors (protein C, AT). At baseline, cancer patients had FVIIa, F1+2, TAT, and PAI-1 significantly greater than control subjects. During treatment, in the patients given ATRA alone, hypercoagulation markers appeared unmodified. Instead, subjects given Tam alone had a significant elevation of FVIIa, F1+2, and TAT versus baseline. However, in the ATRA + Tam groups, hypercoagulation markers were decreased compared with Tam alone. These results suggest that in selected conditions, pre-operative ATRA may modulate the hypercoagulable state of breast cancer patients.
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PMID:Effect of all-trans-retinoic acid on the hypercoagulable state of patients with breast cancer. 1199 76

Dendritic cell-based (DC-based) immunotherapy represents a promising approach to the prevention and treatment of many diseases, including cancer, but current strategies have met with only limited success in clinical and preclinical studies. Previous studies have demonstrated that a TAT peptide derived from the HIV TAT protein has the ability to transduce peptides or proteins into various cells. Here, we describe the use of TAT-mediated delivery of T cell peptides into DCs to prolong antigen presentation and enhance T cell responses. While immunization of mice with DCs pulsed with an antigenic peptide derived from the human TRP2 protein generated partial protective immunity against B16 tumor, immunization with DCs loaded with a TAT-TRP2 peptide resulted in complete protective immunity, as well as significant inhibition of lung metastases in a 3-day tumor model. Although both DC/TRP2 and DC/TAT-TRP2 immunization increased the number of TRP2-specific CD8(+) T cells detected by K(b)/TRP2 tetramers, T cell activity elicited by DC/TAT-TRP2 was three- to tenfold higher than that induced by DC/TRP2. Furthermore, both CD4(+) and CD8(+) T cells were required for antitumor immunity demonstrated by experiments with antibody depletion of subsets of T cells, as well as with various knockout mice. These results suggest that a TAT-mediated antigen delivery system may have important clinical applications for cancer therapy.
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PMID:Induction of CD4(+) T cell-dependent antitumor immunity by TAT-mediated tumor antigen delivery into dendritic cells. 1204 60

Wilms' tumor (WT) is the most common childhood renal malignancy. Although several genetic loci such as the WT1 gene have been known to relate to the biology of WT, the cause of the tumor is complex and the implicated molecular pathways are largely unknown. The beta-catenin gene encodes a protein playing an important role in the Wnt signaling pathway, and its mutations that abrogate specific serine/threonine phosphorylation sites and express oncogenic effect have been found in a variety of tumors. Implication of beta-catenin mutations in WT was investigated in 24 tumors collected from 20 WT patients. One patient had a total of five multiple tumors simultaneously in the bilateral kidneys. Exon 3 and its flanking regions encompassing mutational hot spots of the gene were examined by PCR-based methods. Samples indicating to harbor mutations were further analyzed by sequencing. Six tumors (6/24, 25%) from 4 patients (4/20, 20%) were confirmed to have mutations in heterozygous status. All the mutations, including five different types, were uniformly observed at codon 45 (Ser). Three mutations, Ser45Phe (TCT --> TTT), Ser45Tyr (TCT --> TAT), and Delta45 (deletion of TCT), were found in 3 of 19 unilateral WTs. Other three mutations were detected in three of five multiple tumors developed in the bilateral WT patient; a mutation of Delta45 in one of two tumors in the right kidney, and Ser45Cys (TCT --> TGT) and Ser45Pro (TCT --> CCT) in two of three tumors in the left kidney. Frequent beta-catenin mutations preferentially occurring at codon 45 most likely indicate special importance of this codon for the development of WT and existence of an underlying mechanism causing such a tissue-specific mutational pattern.
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PMID:Codon 45 of the beta-catenin gene, a specific mutational target site of Wilms' tumor. 1223 84

In order to prospectively evaluate the predictive value of coagulation markers such as the fibrin Ddimer for survival of cancer patients, we analyzed their role in a prospective study at a University Hospital Institute of Medical Oncology. 268 consecutive outpatients with cancer were included, 72 in remission and 196 with active disease. All cause mortality in relation to the marker levels was measured. 99/268 patients died during the observation period of 4,484 patient months (mean: 17 months). Patients with active disease had a significant, 1.5-5-fold increased marker concentration compared to patients in remission. When analyzed in quartiles, the data showed a lower than predicted death rate in the first quartile and a significantly elevated mortality in the fourth marker quartile. The odds ratio for death predicted by the fibrin monomer (FM) in the fourth vs. the first quartile was 4.1 (95% C.I.: 1.7-9.7) and p = 0.005 for the multivariate analysis of the markers. We conclude that a single determination of coagulation markers, particularly of TAT, FM, and Ddimer is sufficient to strongly predict survival in cancer patients over the following 1-3 years.
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PMID:Coagulation markers predict survival in cancer patients. 1242 88


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