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)

Several investigators have reported that interferon-gamma (IFN gamma) can alter tumor necrosis factor alpha induced effects in vitro. We assessed in vivo effects of recombinant interferon-gamma (rIFN gamma) on recombinant tumor necrosis factor-alpha (rTNF alpha) induced activation of systemic blood coagulation in a non-randomized study in 20 consecutive cancer patients. Eight patients were treated with rIFN gamma prior to and during hyperthermic isolated limb perfusion with rTNF alpha and melphalan (IFN gamma group). They were compared with twelve patients who did not additionally receive rIFN gamma (non-IFN gamma group). Before start of perfusion, higher levels of TNF alpha, F1+2 and TAT levels were found in the IFN gamma group. Fibrinogen and ATIII levels tended to be lower in this group. High TNF alpha levels, due to leakage during perfusion, were associated with activation of coagulation in all patients, that became obvious after the end of perfusion, when heparin treatment had been antagonized. Activation, measured by increased F1+2 and TAT levels, was significantly stronger in the IFN gamma group. Monocytic TF remained low, possibly due to shedding of TF positive vesicles and/or sequestration of TF positive activated monocytes against the vessel wall. In both groups F1+2 and TAT levels declined 24 h after the perfusion, whereas monocytic TF increased to levels that were higher in the IFN gamma group. In conclusion, our data confirm a strong activation of coagulation induced by rTNF alpha in cancer patients. They suggest that rIFN gamma may lead to a slight activation of coagulation and augments TNF alpha induced procoagulant activity. These effects may be due to rIFN gamma induced sustained monocytic TF activity.
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PMID:Augmented procoagulant activity in cancer patients, treated with recombinant interferon-gamma in addition to recombinant tumor necrosis factor-alpha and melphalan. 897 8

OK-432 (picibanil), a streptococcal preparation, has a strong biological response modifier (BRM) function and is expected to produce clinical improvement and prolongation of survival in treated cancer patients in Japan. We were interested in whether OK-432 augments estrogen receptor (ER) levels in breast cancer. To investigate the effect of the BRMs on cellular growth and the characteristics of ER and progesterone receptors (PgR) in the human breast cancer cell line MCF-7, we used OK-432, Krestin (PSK), a protein-bound polysaccharide extracted from Coriolus versicolor, and lentinan, a fungal branched (1...3)-beta-D-glycan. OK432 and PSK dose dependently inhibited DNA synthesis of MCF-7 cells, and the 50% inhibitory concentrations of OK-432 and PSK were 1.2 KE (klinische Einheit, clinical unit)/ml and 200 micrograms/ml, respectively. Lentinan showed no direct anticancer effect in vitro. We found that OK-432 induced a 2-fold increase in ER levels in MCF-7 cells at 0.005 KE/ml, but not in PgR. Lentinan and low-dose PSK did not change ER or PgR levels, but high-dose PSK decreased ER and PgR. We also studied the combined effect of OK-432 and antiestrogens, tamoxifen (TAM) and DP-TAT-59. The combined treatment with OK-432 and TAM showed an additive inhibitory effect on MCF-7 cells. These results suggest that OK-432 may augment the therapeutic effect of TAM in breast cancer.
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PMID:Effects of OK-432 (picibanil) on the estrogen receptors of MCF-7 cells and potentiation of antiproliferative effects of tamoxifen in combination with OK-432. 926 Jun 4

Malignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of 'in vivo' clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients' hemostatic parameters were evaluated before entry into the study and after starting chemotherapy +/- prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p <0.001), F1+2 (p <0.001), D-dimer (p <0.0001) and FVIIa (p <0.05), as well as an increase of FVII proteolysis (p <0.05), whereas plasma PC and AT concentrations were not different from controls. After starting chemotherapy, markers of clotting activation were progressively lower in the group receiving warfarin prophylaxis compared to the group on placebo. Differences between the groups became statistically significant (p <0.01) after the 4th course of chemotherapy. Deep vein thrombosis occurred in two patients in the placebo arm. The results of this study indicate that before therapy, an hypercoagulable state is present in stage IV breast cancer, and after starting chemotherapy, abnormalities of hypercoagulation markers persist, however they are reduced by very-low-dose-warfarin. None of the laboratory variables could predict thrombosis in the single patient.
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PMID:The effect of very-low-dose warfarin on markers of hypercoagulation in metastatic breast cancer: results from a randomized trial. 945 16

Ferric nitrilotriacetate (Fe-NTA) induces renal proximal tubular damage that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. The RCCs are characterized by 1) high incidence of pulmonary metastasis and peritoneal invasion, 2) high incidence of tumor-associated mortality and 3) possible involvement of reactive oxygen species in carcinogenesis. The present study investigated the possible role of Tsc2 and VHL tumor suppressor genes in this model. Thirty-four Fe-NTA-induced primary RCCs and 20 other primary or metastatic tumors of rats were searched for genetic alteration in all the coding exons of both genes by polymerase chain reaction-single-strand-conformation polymorphism analysis and sequencing in conjunction with morphological evaluation. In the Fe-NTA-induced RCCs, frequency of metastasis or invasion was proportionally associated with the nuclear grade of the tumor (grades 1-3). Only one Fe-NTA-induced RCC of grade 1 revealed missense mutations with loss of heterozygosity in exon 10 of the Tsc2 gene (codons 334, GTG (Val) to GCG (Ala), and 336, TAT (Tyr) to CAT (His). No mutation was found in the VHL gene. The results suggest that 1) high-grade RCCs can develop in the absence of mutations in the Tsc2 and VHL genes in rats, and that 2) Tsc2 gene somatic mutation can nonetheless be one of the causes of non-Eker rat RCCs.
Jpn J Cancer Res 1998 Aug
PMID:Development of high-grade renal cell carcinomas in rats independently of somatic mutations in the Tsc2 and VHL tumor suppressor genes. 976 16

Many studies have demonstrated increased coagulation activation in cancer patients and have shown evidence of chronic, low-grade disseminated intravascular coagulation, although most patients remained asymptomatic. In general, patients have not been screened for deep venous thrombosis (DVT). We screened 98 patients with advanced malignancy for DVT using light reflection rheography. Coagulation profiles of DVT and non-DVT groups were studied. We found a high prevalence of DVT (50%) on screening. Overall, the patients had raised levels of fibrinogen (66% patients), factor VIII:C (43%), fragment 1 + 2 (71%) and TAT levels (89%). Patients with DVT had a significantly lower level of fibrinogen than those without (4.0 g/dl, SD 1.4, compared with 4.7 g/dl SD 1.6, P = 0.04). There was no significant difference in other coagulation or liver function tests between the DVT and non-DVT groups. The wide variation of results makes their interpretation difficult and unlikely to be of predictive value in estimating individual thrombotic risk.
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PMID:Abnormal coagulation and deep venous thrombosis in patients with advanced cancer. 1019 64

Perturbations of coagulation in cancer patients have been described for a long time. In up to 90% of cancer patients "routine" blood tests are abnormal leading to a hypercoagulable state in these patients. Among these tests are an increase in clotting factors, fibrinogen, fibrinogen/fibrin degradation products, and thrombocytosis. Markers of the activation of coagulation have been developed, and levels of FPA, F1+2, TAT, and D-Dimer have been found higher in cancer patients. More specific procoagulant activities in cancer (CP and TF) have also been described and can be measured but none of them have any predictive value for the occurrence of venous thromboembolism in these patients. Consistent with this hypercoagulable state in cancer is the finding that most cancer patients have reduced plasma levels of inhibitors of coagulation. These complex abnormalities are clinically expressed as thrombosis, low-grade or fulminant DIC which can be assessed by different laboratory tests, and as hemorrhage when the fibrinolysis system is impaired. However, no studies have shown to date a relationship between these abnormalities of the coagulation tests and the clinical expression in any single individual. Because these patients are at high risk for thrombosis in special conditions such as surgery or during chemotherapy, prophylaxis with various forms of heparin are recommended.
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PMID:Laboratory diagnosis of the thrombophilic state in cancer patients. 1035 84

Progression of cells through the G1 phase of the cell cycle requires cyclin D:Cdk4/6 and cyclin E:Cdk2 complexes; however, the duration and ordering of these complexes remain unclear. To address this, we synthesized a peptidyl mimetic of the Cdk4/6 inhibitor, p16INK4a that contained an NH2-terminal TAT protein transduction domain. Transduction of TAT-p16 wild-type peptides into cells resulted in the loss of active, hypophosphorylated pRb and elicited an early G1 cell cycle arrest, provided cyclin E:Cdk2 complexes were inactive. We conclude that cyclin D:Cdk4/6 activity is required for early G1 phase cell cycle progression up to, but not beyond, activation of cyclin E:Cdk2 complexes at the restriction point and is thus nonredundant with cyclin E:Cdk2 in late G1.
Cancer Res 1999 Jun 01
PMID:Transduced p16INK4a peptides inhibit hypophosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of Cdk2 complexes in late G1. 1036 76

We devised two short peptides corresponding to amino acids 211-221 of human Cdc25C fused with a part of HIV1-TAT. These peptides inhibited hChk1 and Chk2/HuCds1 kinase activity in vitro and specifically abrogated the G2 checkpoint in vivo. These peptides sensitized p53-defective cancer cell lines to DNA-damaging agent to death without obvious cytotoxic effect on normal cells. Our results clearly indicate that the specific abrogation of the cell cycle G2 checkpoint is a feasible strategy for cancer therapy, and hChk1 and Chk2/HuCds1 are proper targets for that purpose.
Cancer Res 1999 Dec 01
PMID:Sensitization of cancer cells to DNA damage-induced cell death by specific cell cycle G2 checkpoint abrogation. 1060 29

Monocyte tissue factor expression is supposed to play an important role in the hypercoagulability of blood in cancer patients. The relation between coagulation parameters and the expression of monocyte membrane proteins involved in hemostasis or monocyte activation was studied in 21 patients with a disseminated malignancy and 21 age- and sex-matched healthy controls. In the cancer patient group no increase of monocyte tissue factor expression was found (8. 4% vs. 7.8%; P = 0.83), but a significant increase of monocyte-bound activated protein C (APC) (28.8% vs. 13.4%; P = 0.009) and monocyte CD16 expression (34.5% vs. 27.0%; P = 0.007) was observed. There was also a significant increase of D-dimers (2.0 vs. 0.2 microg/ml; P = 0.001), a decrease of antithrombin (83.5% vs. 102.0%; P = 0.004), but no increase of TAT complexes (1.7 vs. 1.5 microg/l; P = 0.38) or factor VII(a) (68.5% vs. 75.0%; P = 0.52). The increase of D-dimers was significantly correlated with the monocyte APC (R = 0.60; P = 0. 005), but not with monocyte tissue factor levels (R = -0.22; P = 0. 35) or TAT complexes (R = 0.12; P = 0.60). These results reflect a local rather than systemic thrombin and fibrin formation. It is suggested that the APC formed locally enters the circulation and binds to peripheral blood monocytes. APC bound on monocytes is known to inhibit monocyte cytokine production and might therefore be involved in regulatory responses of monocytes in cancer patients.
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PMID:Increased D-dimer levels correlate with binding of activated protein C, but not tissue factor expression, on peripheral blood monocytes in cancer patients. 1091 81

Protein transduction domains (PTDs), such as the third helix of the Drosophila Antennapedia homeobox gene (Antp) and the HIV TAT PTD, possess a characteristic positive charge on the basis of their enrichment for arginine and lysine residues. To determine whether cationic peptides are able to function as protein transduction domains, 12-mer peptide sequences from an M13 phage library were selected for synthesis on the basis of their varying cationic charge content. In addition, polylysine and polyarginine peptides were synthesized in order to assess the effect of charge contribution in protein transduction. Coupling of the biotinylated peptides to avidin-beta-galactosidase facilitated transduction in a wide variety of cell lines and primary cells, including islet beta-cells, synovial cells, polarized airway epithelial cells, dendritic cells, myoblasts, and tumor cells. Two of the peptides, PTD-4 and PTD-5, mediated transduction nearly 600-fold more efficiently than a random control peptide, but with an efficiency similar to the TAT PTD and the 12 mers of polylysine and polyarginine. Furthermore, confocal analysis of biotinylated peptide-streptavidin-Cy3 conjugates demonstrated that the internalized PTDs are found in both the nuclei and the cytoplasm of treated cells. When tested in vivo, the PTDs were able to facilitate efficient and rapid protein delivery into rabbit synovium and mouse solid tumors following intraarticular and intratumoral administration, respectively. These novel PTDs can be used to transfer therapeutic proteins and DNA for the treatment of a wide variety of diseases, including arthritis and cancer.
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PMID:Characterization of a class of cationic peptides able to facilitate efficient protein transduction in vitro and in vivo. 1102 Mar 49


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