Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to evaluate the interaction of photodynamic therapy (PDT) and chemotherapy in an animal model. PDT is based on the interaction of hematoporphyrin derivative and red light of the appropriate wavelength (630 nm) and intensity. Two tumor models were utilized: C3H/Km mice bearing the RIF-1 tumor and BALB/c mice bearing the EMT-6 tumor. Tumor-bearing mice were treated with either cisplatin (DDP), doxorubicin (ADM), PDT, or a combination of drug and PDT. It was demonstrated that the RIF-1 tumor was sensitive to DDP and insensitive to both PDT and ADM. There was no additional antitumor effect when either drug was combined with PDT. The EMT-6 tumor was moderately sensitive to PDT and mildly sensitive to both DDP and ADM. Although the addition of DDP did not potentiate tumor destruction, the addition of ADM significantly enhanced the effect of PDT (P = .01). The enhanced activity of the combination of PDT and ADM appeared to be the result of increased activity of ADM alone, when illuminated with red (630 nm) light. This potentiation may be due to a photochemical process or may be secondary to the mild hyperthermia generated by illumination with the laser. This study demonstrates that PDT combined with cytotoxic chemotherapy is well tolerated in these animals and that certain combinations of PDT and chemotherapy may result in an enhanced tumoricidal effect.
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PMID:Combination cytotoxic chemotherapy with cisplatin or doxorubicin and photodynamic therapy in murine tumors. 338 81

THNLA-1 is a recently synthesized 2-nitroimidazole based, DNA-affinic bioreductive agent. It features a tetrahydroacridinic chromophore, which allows loose binding to DNA and therefore greater mobility along its backbone. THNLA-1 was proved to be a very good radiosensitizer and cytotoxin of hypoxic cells in vitro with an improved therapeutic index compared to the fully aromatic analog NLA-1. In this report we investigated the interaction of THNLA-1 with cis-DDP or L-PAM in the sensitive V79 and resistant OVCAR cells, using various schedule protocols. Also, the THNLA-1/cis-DDP interaction in balb/c mice has been investigated, using the EMT-6 mouse tumors. Isobologramic as well as fractional product concept analysis, clearly showed that synergistic interaction occurs between THNLA-1 and each chemotherapeutic agent, under hypoxic pretreatment conditions of the cells with THNLA-1 in vitro. The dose modification factor (DMF) values obtained in the resistant OVCAR-3 cells are similar to those obtained for the approximately 4 times more sensitive V79 cells. Therefore, the DMF value for e.g. L-PAM at 0.1 survival fraction, is approximately 2.76 when 15 microM THNLA-1 was used in OVCAR-3 cells, and approximately 2.50, when 10 microM THNLA-1 was used in V79. The supra-additive effect is dependent on the hypoxia-pretreatment time with THNLA-1, on THNLA-1 concentration and on the concentration of the chemotherapeutic drug. The limited in vivo study showed that THNLA-1, at doses significantly lower than its MTD, strongly potentiates the killing effect of cis-DDP and that the optimum effect during the combination treatment was observed when THNLA-1 was administered i.p., 2.5-3.0 h before cis-DDP. Toxicity studies in balb/c mice (without tumors) showed that THNLA-1 is well tolerated up to at least 70 mg/kg for more than 40 days while no toxicity was observed with the combined drugs used in our experimental protocol. These results are promising for the potential clinical use of THNLA-1 as an adjuvant in chemotherapy.
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PMID:THNLA-1: a DNA-targeted bioreductive agent as chemosensitizer in vitro and in vivo. 872 11

THNLA-1 contains a 2-nitroimidazole tethered to 9-amino-1,2,3,4-tetrahydroacridine. Compared with its parent acridinic analogue, NLA-1, THNLA-1 is a weak DNA-affinic bioreductive compound with a greater mobility along the DNA backbone, decreased aerobic toxicity, greater hypoxic selectivity and a superior in vitro therapeutic index. Also, THNLA-1 behaves as a radio/chemosensitiser in vitro. In this report we have expanded our radio/chemosensitisation studies in vivo, using the EMT-6 mouse mammary tumour model in balb/c mice and the in vivo-in vitro assay. THNLA-1 was given i.p. ( < or = 0.5 ml in saline) at various time intervals before a single dose of 20 Gy whole-body irradiation. Tumours were excised immediately or 24 h after irradiation. Radiosensitisation studies with SR-2508 (i.v.) have been performed in a similar way for comparison purposes. THNLA-1 demonstrated the same radiosensitising effect as SR-2508 but with 19-fold less dose (mmol kg-1). The optimum effect was observed when THNLA-1 was given 1 h before irradiation and the tumours excised 24 h after irradiation. Chemosensitisation studies in the same tumour model and using cis DDP showed that the cytotoxic effect of cis-DDP (5 or 8 mg kg-1, i.p.) was significantly enhanced with 30 or 45 mg kg-1 THNLA-1 given approximately 3 h before cis-DDP. A similar potentiating effect was observed when NLA-1 (27 or 30 mg kg-1) was used, but toxicity was also observed at the higher dose. Limited toxicity studies showed that THNLA-1 is well tolerated up to at least 70 mg kg-1 as a single dose, for more than 40 days.
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PMID:THNLA-1 as radio/chemosensitiser of EMT-6 tumours in mice. 876 95

A map has been assembled that extends from the XY homology region in Xq21.3 to proximal Xq24, approximately 20 Mb, formatted with 200 STSs that include 25 dinucleotide repeat polymorphic markers and more than 80 expressed sequences including 30 genes. New genes HTRP5, CAPN6, STPK, 14-3-3PKR, and CALM1 and previously known genes including BTK, DDP, GLA, PLP, COL4A5, COL4A6, PAK3, and DCX are localized; candidate loci for other disorders for which genes have not yet been identified, including DFN-2, POF, megalocornea, and syndromic and nonsyndromic mental retardation, are also mapped in the region. The telomeric end of the contig overlaps a yeast artificial chromosome (YAC) contig from Xq24-q26 and with other previously published contigs provides complete sequence-tagged site (STS)/YAC-based coverage of the long arm of the X chromosome. The order of published landmark loci in genetic and radiation hybrid maps is in general agreement. Combined with high-density STS landmarks, the multiple YAC clone coverage and integrated genetic, radiation hybrid, and transcript map provide resources to further disease gene searches and sequencing.
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PMID:Integrated STS/YAC physical, genetic, and transcript map of human Xq21.3 to q23/q24 (DXS1203-DXS1059). 1036 51

We report the first de novo mutation in the DDP gene in a Dutch 11-year-old boy with deafness and dystonia. Previously reported mutations in the DDP gene have all been frameshifts/nonsense mutations or deletion of the entire gene as part of a larger deletion encompassing the BTK gene. The clinical presentation was uniformly characterised by sensorineural hearing loss, dystonia, mental deterioration, paranoid psychotic features, and optic atrophy, indicating progressive neurodegeneration. Our report illustrates that de novo mutations occur and that a missense mutation, C66W, may cause an equally severe clinical picture. The diagnosis of sensorineural hearing impairment associated with neurologic and visual disability in a male, therefore, should encourage the search for mutations in the DDP gene, even in sporadic cases. The association of deafness-dystonia syndrome with a missense mutation provides valuable information for in vitro investigations of the functional properties of the deafness-dystonia peptide which was recently shown to be the human homolog of a yeast protein, Tim8p, belonging to a family of small Tim proteins involved in intermembrane protein transport in mitochondria.
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PMID:A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome. 1087 69

The edible mushroom lectin from Agaricus bisporus (ABL) has antiproliferative effects on a range of cell types. This investigation was undertaken to test whether it might have inhibitory activity on Tenon's capsule fibroblasts in in vitro models of wound healing and therefore have a use in the modification of scar formation after glaucoma surgery.Human ocular fibroblasts in monolayers and in three-dimensional collagen lattices were exposed to ABL (0-100 microg ml(-1)). Proliferation was studied by the MTS assay and by counting haematoxylin-stained cells; contraction was measured as a change in the diameter of three-dimensional collagen lattices. Toxicity was investigated using a fluorescent viability assay. FITC-labelled lectin was used to study cell binding and internalization of ABL.ABL caused a dose-dependent inhibition of proliferation and lattice contraction without significant toxicity. Proliferation was inhibited by 5-40% in the dose range 20-100 microg ml(-1) Significant inhibition of lattice contraction was achieved with 40 microg ml(-1) ABL, and at 100 microg ml(-1) contraction was completely prevented. FITC-ABL binds to the cell surface and accumulates around the nuclear envelope when internalized. These experiments have shown that ABL possesses key features required of an agent that might control scarring processes and suggest that ABL might be especially useful where subtle modification of healing is needed. Further evaluation is warranted.
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PMID:Agaricus bisporus (edible mushroom lectin) inhibits ocular fibroblast proliferation and collagen lattice contraction. 1201 17

Inappropriate expression of the multidrug resistance (MDR1) gene encoding the P-glycoprotein (Pgp) has been frequently implicated in resistance to different chemotherapeutic drugs. We have previously generated chronic myeloid leukemia (CML) cell lines resistant to the tyrosine kinase inhibitor imatinib mesylate (STI571), and one line (LAMA84-r) showed overexpression not only of the Bcr-Abl protein but also of Pgp. In the present study, we investigated this phenomenon in other cell lines overexpressing exclusively Pgp. Thus, cells from the K562/DOX line, described as resistant to doxorubicin due to MDR1 gene overexpression, grew continuously in the presence of 1 microM imatinib, but died in 4 to 5 days if the Pgp pump modulators verapamil or PSC833 were added to the imatinib-treated culture. Analysis of cell proliferation by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay confirmed the differential sensitivity of K562/DOX to imatinib, which was also reversed by verapamil or PSC833. Flow cytometric analysis of the total phosphotyrosine content by intracytoplasmic staining after a 2-hour incubation with escalating doses of imatinib showed that the inhibitory concentrations of 50% (IC(50)) for inhibition of cellular protein tyrosine phosphorylation were 15, 10, and 5 microM for K562/DOX, K562/DOX plus verapamil, and K562, respectively. Retroviral-mediated transfection of the BCR-ABL(+) AR230 cell line with the MDR1 gene decreased its sensitivity to imatinib, an effect that was also reversed by verapamil. The possible role of MDR overexpression in clinical resistance to imatinib remains to be defined. We therefore confirm that imatinib should be added to the extensive list of drugs that can be affected by the MDR phenomenon.
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PMID:MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. 1286 89

A new class of checkpoint kinase 1 (CHK-1) inhibitors bearing a 1,4-dihydroindeno[1,2-c]pyrazole core was developed after initial hits from high throughput screening. The efficient hit-to-lead process was facilitated by X-ray crystallography and led to potent inhibitors (<10nM) against CHK-1. X-ray co-crystal structures of bound inhibitors demonstrated that two sub-series of this class of compounds, exemplified by 21 and 41, exhibit distinctive hydrogen bonding patterns in the specificity pocket of the active site. Two compounds, 41 and 43, were capable of potentiating doxorubicin and camptothecin, both DNA-damaging agents, in cell proliferation assays (MTS and soft agar assays) and abrogating G2/M checkpoint in a mechanism-based FACS assay.
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PMID:Discovery of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of potent and selective checkpoint kinase 1 inhibitors. 1728 22

X-linked agammaglobulinemia (XLA) is characterized by low levels of B-lymphocytes with early-onset, recurrent, microbial infections occasionally causing neurological symptoms. We observed an atypical clinical course of XLA, complicated since early childhood with neurological impairment, progressive sensorineural deafness, and dystonia in six boys of four unrelated families. The neurologic symptoms suggested the diagnosis of Mohr-Tranebjaerg syndrome, caused by mutations in the TIMM8A gene, previously known as DDP1, and located centromerically of BTK. Deafness dystonia peptide (DDP1) participates in neurological development and is a part of the mitochondrial protein import pathway. Mutation analysis of the BTK gene revealed gross deletions of different lengths in all patients, in one case extending approximately 196 kb, including the genes TIMM8A, TAF7L, and DRP2. The most prominent clinical findings of this contiguous deletion syndrome are the combination of immunodeficiency and sensorineural deafness, which were present in all affected boys. The severity of symptoms, however, did not correlate with the extent of the deletion.
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PMID:Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. 1785 39

As soil is a natural resource not always renewable, the risk characterization of contaminated soils is an issue of great interest. Artificial Intelligence (AI), based on Decision Support Systems (DSSs), has been developed for a wide range of applications in contaminated soil management. Decision trees have already shown to be easy to interpret and able to treat large scale applications. Fuzzy logic gives an improvement in the perturbations and the variance of the training data, due to the elasticity of fuzzy set formalism. In this study, we have developed a classificatory tool applied to characterize contaminated soil in function of human and environmental risks. Knowledge engineering for constructing the Soil Risk Characterization Decision Support System (SRC-DSS) involves three stages: knowledge acquisition, conceptual design and system implementation. A total of 26 parameters were divided into three groups to facilitate the configuration of the expert system: source attributes, transfer vector attributes, and local properties. Sixteen case studies were evaluated with the SRC-DSS. In comparison with other techniques, the results of the current study have shown that SRC-DDS is an excellent tool to classify and characterize soils according to the associated risk.
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PMID:A fuzzy expert system for soil characterization. 1837 10


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