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)

OK-432, a streptococcal preparation, is known to have strong BRM functions and is expected to produce clinical improvement and prolongation of survival in treated cancer patients. In order to clarify the immunopharmacological mechanisms involved with its clinical effectiveness, intrapleural injection of OK-432 was attempted in patients with malignant pleural effusion due to metastasis from lung cancer. About 70-80% of patients thus treated showed clinical improvements with reduction or disappearance of effusion and effusion tumor cells within a week after the therapy. The clinical response was accompanied by an abrogation or reduction of suppressor macrophages and a stimulatory increase of effective cytotoxic cells resulting in an increase of NK and ATK activity. These in vivo effects observed in the OK-432-treated patients were reproducible in vitro by incubating normal or effusion lymphocytes with tumor-associated macrophages. OK-432 was also shown to reduce the locomotor inhibitory activity of macrophages toward LGL, and to augment the production of various sorts of cytokines, such as IL-1 and MCF by macrophages and IL-2 and NKCF by lymphocytes, all of them being exerted upon activation of the anti-tumor immunological mechanism.
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PMID:[Effective mechanisms of BRM, with special reference to induction of autologous tumor cell-killing (ATK) activity by OK-432]. 348 24

The Philadelphia chromosome [t(9;22)-(q34;q11)] is the cytogenetic hallmark of human chronic myelogenous leukemia. RNA splicing joins sequences from a gene on chromosome 22 (BCR) across the translocation breakpoint to a portion of the ABL oncogene from chromosome 9, resulting in a chimeric protein (P210) that is an active tyrosine kinase. Although strongly correlated with this specific human neoplasm, and implicated as an oncogene by analogy to the gene product of the Abelson murine leukemia virus, the P210 gene had not been tested directly for oncogenic potential in hematopoietic cells. We have used a retroviral gene-transfer system to express P210 in mouse bone marrow cells. When infected bone marrow is plated under conditions for long-term culture of cells of the B-lymphoid lineage, cells expressing high amounts of P210 tyrosine kinase dominate the culture and rapidly lead to clonal outgrowths of immature lymphoid cells. Expression of P210 is growth-stimulatory but not sufficient for full oncogenic behavior. Some clonal lines progress toward a fully malignant phenotype as judged by increased cloning efficiency in agar suspension and frequency and rapidity of tumor induction in syngeneic mice. Such in vitro systems should be useful in evaluating the sequential and perhaps synergistic involvement of the P210 gene and other oncogenes as models for the progressive changes observed in human chronic myelogenous leukemia.
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PMID:In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. 349 65

In the previous paper in this series, we described a form of self-reactivity among T cells called the "syngeneic T-T lymphocyte reaction" (STTLR). The phenomenon involves responder T cells that are stimulated to proliferate by irradiated antigen or self-reactive cloned T cell lines. The proliferative STTLR occurs in cultures rigorously depleted of conventional APC and is inhibitable by anti-Ia antibodies of the appropriate specificity. We also showed that both L3T4+ Lyt2- and L3T4- Lyt2+ T cell subsets participate in the STTLR-induced by the IEk-specific Lbd T cell line. In this paper, we report our studies on the effector phase of STTLRs, in particular, the cytotoxic responses induced by Lbd cells. We demonstrate that uncloned and cloned lines (called Dbl) of anti-Lbd cytotoxic cells are L3T4- Lyt2+ effector cells that kill Lbd, antigen-reactive T cells, and syngeneic B cells stimulated with LPS. They also kill syngeneic splenic cells stimulated with Con A for 72 h or less; longer culture periods in the presence of Con A yield Dbl-resistant T cells. Resting T cells are also resistant to Dbl cells. Using LPS-induced splenic B cells from H-2 congenic mice, we map the anti-self specificity of uncloned and cloned anti-Lbd cells to the Kk + IAk regions of the MHC. Seemingly concordant results were obtained using L transformants expressing IAk molecules on their surface. However, control studies with fibroblast lines and UV-induced fibrosarcoma cells unexpectedly revealed a high susceptibility to lysis by Dbl cells among certain Ia- cell lines. These results suggested that the antigen recognized by Dbl cells is not IAk itself but either an MHC-encoded or MHC-regulated gene product expressed by activated T and B cells and certain tumor cells. The target antigen is important in immunoregulation because Dbl cells suppress both the proliferation of Lbd cells to syngeneic cells and primary T cell-dependent anti-SRC PFC responses. From an immunoregulatory viewpoint, the existence of Lbd-Dbl cells offers several appealing features. Since Lbd cells cannot activate resting B cells or replace antigen-specific helper cells, they cannot initiate immune responses nonspecifically. In the presence of the appropriate antigen-specific helper T cells, Lbd and other self-reactive cells can amplify an immune response and thus facilitate its exponential growth. Since the self-reactive cells activate the Dbl cytotoxic circuit described above, they also provide the stimulus required to terminate immune responses quickly.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The syngeneic T-T lymphocyte reaction (STTLR). II. Induction of primary T anti-T cell cytotoxic responses in vitro in T cell cultures stimulated with syngeneic self-reactive T cells. 350 19

Subrenal capsule assay (SRC assay) was investigated to evaluate the usefulness as an in vivo chemosensitivity test of anticancer agents. The pathological study on the growth of the implanted tumor and host response indicated that the assay had to be done by four-day assay. The analysis of the isotope incorporation into the implanted tumor supported this results. As determination of tumor sensitivity by the microscopic measurement showed the large standard deviation, the DNA and protein content was determined for the evaluation of sensitivity by percent inhibition of the DNA/protein content (%DNA/protein). Ninety five fresh tumor specimens were examined and evaluated by relative variation of the calculated tumor weight (delta TW/TW0), while 64 specimens by %DNA/protein. The evaluability rates using delta TW/TW0 and %DNA/protein were 84.2% and 87.5%, respectively. All over predictive accuracy between the clinical responses and the results of the assay evaluated by delta TW/TW0 was 78.6%, while 81.8% was obtained by %DNA/protein. From these results, the potential utility of SRC assay examined on 4 day for determining chemosensitivity by %DNA/protein seems to be beneficial for clinical use.
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PMID:[Experimental and clinical studies on subrenal capsule assay for predicting individual tumor chemosensitivity]. 357 73

Clinical trials of 4-day subrenal capsule assay (SRC assay) were carried out. One hundred and forty-one cases were investigated in order to evaluate the clinical utility of the assay. A total evaluability rate of 81.0% and a response rate of 36.5% were obtained in the SRC assay. The overall predictive accuracy between the tumor sensitivity of the assay and the clinical response was 82.1%. The percentage inhibition of %DNA/protein content of the implanted tumor, as a new predictor of the tumor growth inhibition, also indicated a good prediction rate for the assay. Correlation between the sensitivity test and the end results after chemotherapy in cases of inoperable gastric cancer classified as stage IV was investigated, retrospectively. Comparison of the survival curves between the patients treated with sensitive agents and those with insensitive agents exhibited a significant advantage for the former (p less than 0.01). These results suggest the utility of the SRC assay for clinical use, but histological studies exhibited certain limitations of this assay due to the existence of early host rejection of the implanted tumor. The utility of the SRC assay should be finally evaluated using more histological assessments and clinical trials.
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PMID:[Clinical trials of the subrenal capsule assay]. 361 57

Chemotherapeutic response of two squamous cell carcinoma xenograft lines (established from the primary and metastatic lesion of a tongue carcinoma) was studied using SC and SRC assays (as well as immunocompetent and -suppressed recipients in the latter assay). The two assays provided similar ranking of drugs, in the sense that in each instances two of the three (cyclophosphamide, 5-fluorouracil, vinblastine) most active agents were identical. The host response in immunocompetent recipients supports the need for histology to prove the proper quality of the implanted tumor tissue in order to be used for drug evaluation.
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PMID:Chemotherapeutic response of squamous cell carcinoma xenografts (subcutaneous and subrenal capsule assay). 367 Jul 98

The toxicity of 1-[2-(diethylamino)ethyl]reserpine (DL-152) has been measured for 4 transplantable mouse tumors. DL-152 was found to be toxic to cells of all the tumor models tested (KHT fibrosarcoma, RIF-1 fibrosarcoma, EMT-6 adenocarcinoma and Lewis lung carcinoma) when the drug was given by intraperitoneal injection to the tumor-bearing mouse and cell survival was measured by excision assay. For the KHT tumor, hypoxic cells were found to be more sensitive to the drug in vivo than were aerated cells, and a similar response to hypoxia was observed in vitro, suggesting that sensitization occurred at the cellular level. Neither EMT-6 nor RIF-1 tumors showed increased sensitivity to the drug when cells were exposed under hypoxic conditions in vivo or in vitro. However, when the response of aerated cells of the 3 tumors was compared, the relative sensitivities for tumors exposed in vivo did not show the same ranking as the results of in vitro toxicity assays. This difference in in vitro and in vivo response in the different tumor models did not appear to be related to pharmacokinetic factors since the maximum tissue concentration and the rate of clearance of the drug were similar for all the tumors studied.
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PMID:Factors influencing the toxicity of diethylaminoethylreserpine to tumor cells: studies with four transplantable tumors. 368 80

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 1-nitroacridine nitracrine [NC,1-nitro-9-(dimethylaminopropyl-amino)acridine] is a potent hypoxia-selective cytotoxic agent in culture, but lacks activity against hypoxic tumor cells in vivo at therapeutically accessible doses. To clarify reasons for this failure in vivo the metabolism of NC was investigated in stirred suspension cultures of Chinese hamster ovary cells, in EMT-6 spheroids, and in mice. One major low molecular weight metabolite (identical to that generated by NaBH4/Pd/C reduction) was observed in hypoxic (less than 10 ppm O2) single cell suspensions, while [G-3H-acridinyl]NC formed trichloroacetic acid- and acetonitrile-insoluble macromolecular adducts (MA) at a rate seven-fold higher than in aerobic (20% O2) cultures. Formation of these adducts correlated with cytotoxicity under air or nitrogen, and hence may provide a dosimeter for NC-induced damage. Autoradiographic investigation of the distribution of MA in spheroids equilibrated with 5% O2 showed that the label was restricted to the outer cell layers rather than being localized in the hypoxic central region. Thus metabolic activation is probably too rapid, even in well-oxygenated cells, to allow adequate distribution to hypoxic microenvironments in tumors. In mice, levels of MA were higher in liver, kidney, spleen and lung than in Lewis lung tumors, indicating that oxygen concentration does not exert a dominant influence on relative rates of metabolic activation in vivo. The development of nitroacridines with useful hypoxic selectivity in vivo will require identification of analogs for which reductive metabolism is more completely inhibited at oxygen concentrations found in normal tissues.
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PMID:Reductive metabolism and hypoxia-selective toxicity of nitracrine. 374 44

The binding rate of 14C-Misonidazole was determined for freshly isolated mouse hepatocytes, mouse hepatoma cells, EMT-6 tumor cells, and V79 Chinese hamster lung fibroblasts. At 10 microM drug concentration, the four different cell lines bound 14C-Misonidazole at rates of 12.4, 29.9, 51.6, and 13.5 pmoles/10(6) cells/hr, respectively. This relative order of binding was observed over a drug concentration range of 10-100 microM. These data indicate that in extreme hypoxia, mouse hepatocytes do not bind 14C-Misonidazole at a uniquely high rate in vitro, compared to other normal and tumor cell lines. This observation suggests that the increased binding to liver in vivo observed by other investigators is due to the liver existing at a reduced oxygen tension, compared to other normal tissues.
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PMID:In vitro binding of 14C-misonidazole to hepatocytes and hepatoma cells. 374 47


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