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: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the role of the BCR-ABL gene in the proliferation of blast cells of patients with chronic myelogenous leukemia, leukemia blast cells were exposed to synthetic 18-mer oligodeoxynucleotides complementary to two identified BCR-ABL junctions. Leukemia colony formation was suppressed, whereas granulocyte-macrophage colony formation from normal marrow progenitors was unaffected. When equal proportions of normal marrow progenitors and blast cells were mixed, exposed to the oligodeoxynucleotides, and assayed for residual colony formation, the majority of residual cells were normal. These findings demonstrate the requirement for a functional BCR-ABL gene in maintaining the leukemic phenotype and the feasibility of gene-targeted selective killing of neoplastic cells.
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PMID:Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. 185 87

The radiation sensitizing agent misonidazole (MISO) was combined with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) for the treatment of Mer+ (IMR-90, HeLa, and HeLa-S3) and Mer- (EMT-6/Ro, VA-13, and HeLa-MR) cell lines under hypoxic conditions in vitro. The magnitude of enhancement achieved by the addition of MISO was calculated by comparison with survival curves obtained by treating each cell line with CCNU alone, under hypoxic conditions. As expected, the Mer+ cells were more resistant to CCNU treatment than were their Mer- counterparts. In the presence of 1.0 mM MISO the toxicity of CCNU was enhanced (dose enhancement factor, 1.4-1.6) in all three of the Mer- lines. However, the Mer+ lines were less responsive to chemopotentiation by MISO. The toxicity of CCNU toward two of the Mer+ lines, IMR-90 and HeLa, was not modified by the addition of MISO, while a slight enhancement (dose enhancement factor, 1.2) was observed in the HeLa-S3 line. Similar results were obtained with IMR-90 and VA-13 cells treated by postincubation in which aerobic CCNU treatment was followed by hypoxic exposure to MISO for up to 6 h. While no correlation was observed between Mer status and the hypoxic toxicity of MISO, the data suggest that a relationship might exist between chemopotentiation and MISO sensitivity when each phenotype is considered separately. These observations suggesting that tumor cells of the Mer+ phenotype may be less responsive to MISO chemopotentiation have significant implications for ongoing and planned clinical trials designed to evaluate the potential of chemopotentiation using CCNU and MISO since greater than 75% of human tumors are Mer+.
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PMID:Misonidazole-induced chemopotentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea toxicity in O6-methylguanine-DNA methyltransferase proficient (Mer+) and deficient (Mer-) cell lines. 369 15

The region comprised between the amino acids 175 and 199 of the HTLV-I envelope surface glycoprotein is one of the immunodominant domains of this molecule. In this region, which is well recognized by sera from HTLV-I infected patients, a substitution of the proline at position 192 by a serine has been described in some isolates. Because this mutation could modify the secondary structure of the glycoprotein molecule, we studied the inference of the presence of proline or serine on the recognition of the region 175-199 by human sera. For this, three peptides have been synthetized (a 25-mer 175-199 corresponding to the sequence of the ATK prototype, and two internal 10-mer 190-Pro-199 and 190-Ser-199 having a proline or a serine at position 192) and tested by immunosorbent assay. While most sera reacted with 190-Pro-199 and with 190-Ser-199 synthetic peptides, a differential recognition was observed according to the pathology associated to HTLV-I infection. Moreover sera corresponding to patients infected with a virus harboring a serine at position 192 were found to recognize only the 10-mer with a serine. These data indicates that HTLV-I is subject to antigenic variability.
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PMID:Recognition by human sera of a variable region of the surface glycoprotein of HTLV-I. 815 6

When injected into SCID mice, the Philadelphia chromosome-positive chronic myeloid leukemia-blast crisis cell line BV173 induces a disease process closely resembling that seen in leukemia patients. At 1 and 3 weeks after injection of 10(6) BV173 cells, CD10+ cells were detected in the bone marrow of the mice, leukemic colonies grew from bone marrow and spleen cell suspensions, and BCR-ABL transcripts were detectable in bone marrow, spleen, peripheral blood, liver, and lungs. Systemic treatment of the leukemic mice with a 26-mer BCR-ABL antisense oligodeoxynucleotide (1 mg/day for 9 days) induced disappearance of CD10+ and clonogenic leukemic cells and a marked decrease in BCR-ABL mRNA in mouse tissues. Untreated mice or mice treated with a BCR-ABL sense oligodeoxynucleotide or a 6-base-mismatched antisense oligodeoxynucleotide oligodeoxynucleotide were dead 8-13 weeks after leukemia cell injection; in marked contrast, mice treated with BCR-ABL antisense oligodeoxynucleotide died of leukemia 18-23 weeks after injection of leukemic cells. These findings provide evidence for the in vivo effectiveness of an anticancer therapy based on antisense oligodeoxynucleotides targeting a tumor-specific gene.
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PMID:Suppression of Philadelphia1 leukemia cell growth in mice by BCR-ABL antisense oligodeoxynucleotide. 818 38

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the BCR-ABL hybrid gene. Two types of hybrid BCR-ABL mRNA have been found, B2A2 and B3A2. As the BCR-ABL rearrangement is specific to leukemic cells, selective inhibition of leukemic cell growth by BCR-ABL antisense oligonucleotides (ASO) has been reported in vitro for CML patients and cell lines. However, controversial results have been obtained from preclinical studies using anti-BCR-ABL ASO, as nonspecific inhibition of leukemic cell growth was evidenced in some cases. B3 exon secondary structure was deduced from its sequence and found to be a loop. According to this predictive structure of exon B3, a 56-mer antisense oligonucleotide targeting the polypurine bases from the B2A2 junction was devised which would inhibit proliferation (MTT assay) of B3A2 junction cell lines (K562 and a murine cell line Ba/F3 transfected with the B3A2 junctional sequence). This ASO had a hairpin-like secondary structure and was found to be much more resistant to the action of nucleases than control 18-mer standard oligonucleotides. Hybridization to its target mRNA occurs via formation of a triplex structure. A concentration of 5 microM of specific 56-mer B2A2 ASO was necessary to demonstrate 50% optical density (OD) reduction for K562 cell line and Ba/F3 transformed by B3A2 cDNA. Sense and non-sense 56-mer sequence or 18-mer linear ASO showed no effect for these concentrations. Western blot showed a partial inhibition of P210 protein; expression of P145abl remains unchanged. The 56-mer ASO also inhibited the proliferation of B2A2 junction cell line BV173 at the same concentration and showed no effect on the HL60 cell line used as control.
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PMID:Inhibition of chronic myelogenous leukemia cells harboring a BCR-ABL B3A2 junction by antisense oligonucleotides targeted at the B2A2 junction. 854 54

Antisense oligonucleotides were used to determine the role of the BCR-ABL gene in the proliferation of chronic myeloid leukaemia (CML) clonogenic cells. Peripheral blood Philadelphia chromosome positive cells were obtained from eight CML patients at diagnosis (chronic phase = 7; accelerated phase = 1). Mononuclear cells were incubated with synthetic antisense 18-mer oligonucleotides complementary to the two different junctions b2a2 or b3a2. The type of junction (b2a2 or b3a2) was previously determined by RT-PCR techniques. Cells incubated for 12 to 14 hours with or without sense oligonucleotides served as controls. After incubation with oligonucleotides, the cell DNA synthesis was analysed by flow cytometry using the BrdUrd/DNA method and the cell plating efficiency in methylcellulose was determined. In six of the seven patients in chronic phase, there was a significant inhibition of CFU-GM production which was only 68.4 +/- 19%; (p < .01) of that found in controls. The S phase index, which depends upon the percentage of S phase cells as well as the fluorescence intensity, was 48 +/- 29% (p < .01) of the control values for the seven patients in chronic phase. Interestingly, for the only CML patient in accelerated phase, antisense oligomers had no inhibitory effect on either the production of CFU-GM or the number of S phase cells. In improving the specificity of oligomers, it might be useful for gene-targeted anti-leukemic therapy and/or bone marrow purging.
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PMID:Specific antisense oligomer anti Bcr-abl junctions in chronic myeloid leukemia: a cell cycle analysis and CFU-GM study. 859 Aug 42

NCC recognize a conserved target cell antigen (NKTag) expressed on protozoan parasites and on transformed tumour cells. In the present study, synthetic peptides corresponding to N-terminal, C-terminal and internal NKTag(deduced) amino acid sequences were tested for binding and inhibition of NCC lysis of sensitive target cells. A 20-mer peptide equivalent to amino acids (aa) nos. 55-74 specifically inhibited NCC lysis of human EBV transformed target cells (IM-9). Inhibitory effects were nonreversible and concentration dependent, and 30 min pre-incubation produced optimum inhibition. The inhibitory 20-mer peptide was truncated into 17, 14, 10, 9 and 6-mer peptides and tested for inhibition of cytotoxicity. All produced almost complete inhibition except the 6-mer which had no activity. The NKTag sequence required for NCC binding (minimally) consisted of seven amino acids [aa nos 68-74 (ARG-ASN-LEU-THR-PHE-ILE-LEU-)]. The specificity of inhibition and the distribution of target cells expressing NKTag was determined. A 14-mer peptide composed of aa nos 61-74 inhibited lysis of HL-60, IM-9, DAUDI, YAC-1, U937 and NC-37 target cells. Flanking peptides (aa nos 35-54 and 75-94) were negative. Biotinylated aa nos 61-74 bound to NCC effector cells. The recognition requirements for aa sequence versus aa content were determined. Randomization of the aa in the cognate 9-mer obliterated the inhibitory effects. The 17-mer (cognate) synthetic peptide inhibited conjugate formation between NCC and IM-9 targets. These data demonstrate that NCC recognize a conserved antigen determinant on susceptible target cells consisting of a minimum of 7-9 amino acids in the N-terminal region of NKTag.
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PMID:Mapping of the epitope recognized by non-specific cytotoxic cells: determination of the fine specificity using synthetic peptides. 863 15

To characterize the distribution and toxicity of phosphorothioate antisense oligodeoxynucleotides ([S]ODNs) in vivo, the mice, previously injected with BV173 leukemic cells (Philadelphia chromosome-positive chronic myeloid leukemia blast-crisis), received intravenously 26-mer BCR-ABL antisense oligodeoxynucleotides (1 mg/mouse/day) for 9 consecutive days. Our investigation revealed that [S]ODNs were distributed to almost all organs except the brain with the highest level in the liver, spleen and kidneys. They were also detected in CD10+ leukemic cells isolated from spleen and bone marrow. Intracellular distribution assay showed the presence of [S]ODNs most prominently in nuclear and cytoplasmic fractions. Our data demonstrated no significant toxicity of [S]ODNs except the increase in spleen weight.
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PMID:The influence of phosphorothioate oligodeoxynucleotides on various organs in vivo. 887 13

Antisense oligodeoxyribonucleotides (ODN) targeted against the breakpoint in BCR-ABL mRNA will specifically decrease BCR-ABL mRNA, provided cells are first permeabilised with streptolysin-O (SL-O). We used 18-mer chimeric methylphosphonodiester: phosphodiester linked (4-9-4) ODN complementary to 9 bases either side of the BCR-ABL junction to purge harvests ex vivo in three CML patients who remained completely Ph positive after multiple chemotherapy courses. After CD34+ cell selection and SL-O permeabilisation, harvests were purged with 20 microM ODN. After purging, all individual CFU-GM colonies grown from the two b3a2 breakpoint cases remained positive for BCR-ABL mRNA. In contrast, all 24 colonies grown from the b2a2 breakpoint case were BCR-ABL mRNA negative. Patients were conditioned with busulphan 16 mg/kg. The initial post-transplant course was uneventful, although the time to return to 0.5 x 10(9)/l neutrophils was slow at 25-51 days. Both chronic phase patients remain in haematological remission at +724 and +610 days, although each has cytogenetic evidence of relapse. The b2a2 accelerated phase patient died of myeloid blast transformation at day +91. The present SL-O-facilitated ODN purging strategy appears to be without significant toxicity, and offers considerable improvements in ODN delivery to the cytosol.
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PMID:Clinical use of streptolysin-O to facilitate antisense oligodeoxyribonucleotide delivery for purging autografts in chronic myeloid leukaemia. 1041 20

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by a specific hybrid gene BCR-ABL (formed as a result of t(9;22)). This leads to two possible mRNA usually present in leukemic cells, either B2A2 or B3A2. Targeting these mRNA by antisense oligonucleotides (AS) might offer the opportunity to decrease leukemic growth. We have tested the ability of AS to inhibit the in vitro proliferation of CD34 positive (CD34+) blood cells from 16 patients with newly diagnosed CML. CD34+ cells were isolated by an immunomagnetic technique and incubated for 16 to 18 hours with an 18 mer AS (0.25 mM). Sense oligonucleotides served as controls. The effects of AS were evaluated by clonogenic test (production of CFU-GM). Moreover, colonies were picked out and studied by RT-PCR to analyse the presence of BCR-ABL transcript. For nine patients with B3A2 transcript, the median inhibition of CFU-GM formation at day 14 was 64.0 +/- 11.2% (68.0 +/- 11.4% at day 21) and for the seven patients with a B2A2 transcript: 59.0 +/- 11.4% (72.5 +/- 12.0% at day 21). AS showed no effect on CD34+ cells from three normal volunteer donor cells. However, for every patient studied, colonies picked out remained BCR-ABL positive with the RT-PCR technique.
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PMID:Effect of antisense oligonucleotides on CD34+ cells from chronic myeloid leukemia. 1078 2


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