Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four novel proteins (phoratoxins C-F) have been isolated from the North American mistletoe Phoradendron tomentosum. The amino acid sequences of these phoratoxins were determined unambiguously using a combination of Edman degradation and trypsin enzymatic digestion, and by electrospray ionization tandem mass spectrometry sequencing. Phoratoxins C, E and F consist of 46 amino acid residues; and phoratoxin D of 41. All proteins had six cysteines, similar to the earlier described phoratoxins A and B, which are thionins. The cytotoxicity of each protein was evaluated in a human cell line panel that represented several cytotoxic drug-resistance mechanisms. For the half-maximal inhibitory concentrations (IC50 values) of the different cell lines in the panel, correlation with those of standard drugs was low. The most potent cytotoxic phoratoxin C was further tested on primary cultures of human tumor cells from patients. The solid tumor samples from breast cancer cells were 18 times more sensitive to phoratoxin C than the tested hematological tumor samples.
Cell Mol Life Sci 2003 Jan
PMID:Small, novel proteins from the mistletoe Phoradendron tomentosum exhibit highly selective cytotoxicity to human breast cancer cells. 1261 65

We have previously shown that nitric oxide (NO) inhibits growth and induces differentiation and apoptosis in acute myeloid leukemia cells, with the HL-60 human myeloid leukemia line being particularly sensitive to NO-mediated cytolysis. With the goal of identifying a prodrug that can target NO to the leukemia cells without inducing NO-mediated systemic hypotension, we have screened a series of O(2)-aryl diazeniumdiolates designed to be stable at physiological pH but to release NO upon reaction with glutathione. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) proved to be the most active antiproliferative agent among those tested in HL-60 cells, with an IC(50) of 0.2-0.5 microM. After 5 days of exposure to 0.5 micro M JS-K, HL-60 cells had differentiated and acquired some of the phenotypic features of normal monocytes. One- to 2-day treatment with JS-K at concentrations of 0.5-1 microM resulted in apoptosis induction in a concentration- and caspase-dependent manner. JS-K also inhibited the growth of solid tumor cell lines but to a lesser extent than HL-60 cells. JS-K was administered i.v. to nonobese diabetic-severe combined immune deficient mice at doses of up to 4 micromol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by approximately 50% when the mice received i.v. injections three times/week with 4 micromol/kg boluses of JS-K. Histological examination of tumor explants from JS-K-treated animals revealed extensive necrosis. Similar results were seen with s.c. human prostate cancer (PPC-1) xenografts. Our data indicate that JS-K is a promising lead compound for the possible development of a novel class of antineoplastic agents.
Mol Cancer Ther 2003 Apr
PMID:JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity. 1270 Feb 85

The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.
J Mol Med (Berl) 2003 Apr
PMID:Proteasome inhibition: a new anti-inflammatory strategy. 1270 Aug 91

Advanced Viral Research Corp is developing reticulose, a nontoxic peptide nucleic acid preparation, for the potential treatment of viral infection. The compound is undergoing phase II clinical trials for the potential topical treatment of human papillomavirus infection in the US. Reticulose has also been investigated in clinical studies for the treatment of HIV infection in Barbados. Additionally, the drug is being investigated for the potential treatment of adenovirus infection, and is being evaluated in adjuvant arthritis models by the Weizmann Institute of Science. Investigations into the use of reticulose to reduce the toxic effects of cancer treatment are underway in Israel. Phase I trials in patients with cachexia associated with HIV, lymphoma and solid tumor, have also been initiated in Israel.
Curr Opin Mol Ther 2003 Apr
PMID:Technology evaluation: reticulose, advanced viral research. 1277 10

Oxysterols are oxygenated derivatives of cholesterol that have been shown to influence a wide variety of cellular processes including sterol metabolism, lipid trafficking, apoptosis and more recently, cell differentiation. The oxysterol binding proteins (OSBPs) comprise a large conserved family of proteins in eukaryotes with high affinity for oxysterols, but their precise function has not been defined yet. One member of this family in humans, HLM/OSBP2 protein, has recently been reported as a potential marker for solid tumor dissemination and worse prognosis in these cases. In this study we focused on the evaluation of HLM/OSBP2 expression in malignant cell lines from different origins (blood and solid tumors) and we also evaluated its expression in chronic myeloid leukemia patients, correlating the molecular findings with clinical outcome. Our results showed that HLM/OSBP2 was expressed in 80% of the analysed CML patients, suggesting that this protein could constitute a helpful tool for disease monitoring and reinforces recent findings that HLM/OSBP2 protein could be involved in the maintenance of the undifferentiated state necessary for leukemogenesis.
Int J Mol Med 2003 Oct
PMID:HLM/OSBP2 is expressed in chronic myeloid leukemia. 1296 51

The abnormal activation of the epidermal growth factor (EGF) pathway is one of the most common findings in human cancer, and a number of molecular devices of laboratory and clinical relevance have been designed to block this transduction pathway. Because of the large number of cellular events that might be regulated through the activation of the four EGF receptor family members, it is possible that screening methodologies for the identification of new molecular targets working downstream of these pathways may provide new tools for cancer diagnosis and potentially prevention and therapy. In searching for EGF target genes, we have identified ERG1.2, the mouse homolog of the solid tumor-associated gene STAG1. Both in humans and in mice, it belongs to a new gene family that can give origin to several protein isoforms through alternative splicing and/or multiple translation starts. Sequence analysis and experimental data suggest that ERG1.2 is likely to function as a membrane-bound protein interacting with downstream signaling molecules through WW- and SH3-binding domains. ERG1.2 is a cell-cycle-regulated gene, and both ERG1.2 and STAG1 are induced by EGF and other growth factors at the transcript and protein levels. Finally, we have demonstrated that, besides prostate cancer and renal cell carcinoma, STAG1 was also overexpressed in breast and ovarian cancer cell lines and in breast primary tumors. Although in most cases STAG1 overexpression is probably due to the abnormal activation of the EGF pathway, we have also demonstrated genetic amplification and rearrangement of its locus in one breast cancer cell line and one primary ovarian cancer, suggesting that STAG1 might be a direct molecular target in the carcinogenetic process. Thus its overexpression might be regarded not only as a tumor marker but also as a potentially pathogenetic event.
Mol Carcinog 2003 Dec
PMID:EGF- and cell-cycle-regulated STAG1/PMEPA1/ERG1.2 belongs to a conserved gene family and is overexpressed and amplified in breast and ovarian cancer. 1463 58

Bevacizumab, an antivascular endothelial growth factor monoclonal antibody, is being developed by Genentech and Roche as an anti-angiogenesis therapy for the potential treatment of solid tumors. In June 2003, bevacizumab was granted Fast Track status by the FDA for the potential treatment of first-line colorectal cancer. The antibody is currently in phase III trials for non-small-cell lung, colorectal and breast cancers, and in phase II trials for various other solid tumor types.
Curr Opin Mol Ther 2003 Dec
PMID:Technology evaluation: bevacizumab, Genentech/Roche. 1475 93

TAS-102 is a new oral anti-tumor drug preparation, composed of a 1:0.5 mixture (on a molar basis) of alpha,alpha,alpha-tri-fluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). TAS-102 is currently undergoing clinical trials, and has been demonstrated to have at least 2 mechanisms; inhibition of thymidylate synthase (TS) and incorporation into DNA. 5-FU is widely used in the treatment of solid tumor, but the inherent or acquired resistance of certain tumors to 5-FU therapy is a major clinical problem. In the present study, we investigated FTD in vitro and in vivo comparing with 5-FU and using FU-resistant cells. There was no relationship between FTD and 5-FU growth inhibition effect in vitro. A different sensitivity pattern was observed by the log-mean graph. We next investigated the anti-tumor activity of TAS-102 in a FU-resistant xenograft model. Comparative efficacy was observed between FU-resistant cell and its parent cell. We also studied the influence of TAS-102 on liver metastasis in a mouse model of human colorectal cancer, because liver metastasis of colorectal cancer is associated with patient survival. Human cancer DNA was detected by PCR, and TAS-102 markedly inhibited the number of liver metastasis. A novel angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), was shown to be identical to a previously characterized intracellular enzyme, thymidine phosphorylase, TAS-102 can be expected to have not only anti-tumor cytocidal effects but also antiangiogenesis activity and may inhibit liver metastasis. Our findings suggested that TAS-102 is a promising candidate for clinical use and can be expected to decrease minimal residual disease.
Int J Mol Med 2004 Apr
PMID:A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. 1501 Aug 54

To study tumor therapeutic treatment modalities, whether from a clinical, preclinical, or fundamental point of view, the use of clinically relevant animal models is indispensable. Particularly when the treatment comprises a multitargeted approach, (e.g., both tumor cells and endothelial cells are targeted), the in vitro data will be of very limited value. Well-chosen animal models will provide conclusive data on the activity of the drug in the complex in vivo setting. Moreover, when the treatment targets the stromal compartment of the tumor rather than the tumor cells directly, insight into the mechanism of action is only possible when studied in vivo. This approach is of great importance for studies on the use of tumor necrosis factor-alpha (TNFalpha) in solid tumor therapy. Although TNFalpha has shown activity toward tumor cells in vitro directly, we and others have demonstrated that an important activity of this cytokine is directed toward the tumor vasculature. To elucidate the working mechanism of TNFalpha and to test possible treatment modalities, the animal models described here are crucial. In this chapter we will describe the use of specific animal models for efficacy studies, such as isolated limb perfusion and isolated liver perfusion in the rat.
Methods Mol Med 2004
PMID:Tumor vascular therapy with TNF: critical review on animal models. 1506 44

Leukemia cell lines K562, KG1a, U937, HL60, Jurkat and solid tumor cell lines A549 and M4Beu are widely used in studies of cell cycle, apoptosis and adhesion mechanisms in cancer cells. Although the K562 and U937 cell lines were previously subjected to a detailed cytogenetic characterization, only a few molecular cytogenetic investigations have been performed on the other five cell lines. We combined several molecular cytogenetic techniques, such as fluorescence in situ hybridization (FISH), multicolor FISH (M-FISH), and comparative genomic hybridization (CGH) to demonstrate the precise genetic aberrations in tumor genomes of these seven cell lines. This information may be useful for multiple studies on these cell lines, providing a genetic basis for the interpretations of experimental findings.
Int J Mol Med 2004 Oct
PMID:Cytogenetic characterization of seven human cancer cell lines by combining G- and R-banding, M-FISH, CGH and chromosome- and locus-specific FISH. 1537 17


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