Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the use of tumor-derived heat shock/chaperone proteins (HSPs) as anticancer vaccines is gaining wider study and acceptance, there have thus far been no reports concerning chaperone antitumor activities against disseminated hematological malignancies. We have devised an efficient and effective method for purification of the chaperone proteins grp94/gp96, HSP90, HSP70, and calreticulin from harvested A20 murine leukemia/lymphoma tumor material. We have demonstrated that these purified proteins, when used as vaccines, can induce potent and specific immunity against a lethal tumor challenge. Individual chaperone proteins were differentially effective in their abilities to provide immune protection. The increase in survival generated by the most effective chaperone vaccine, HSP70, resulted from at least a 2-log reduction in tumor burden. Syngeneic granulocyte macrophage colony-stimulating factor producing fibroblasts were injected at the site of vaccination in an attempt to augment the immune response. Surprisingly, localized granulocyte macrophage colony-stimulating factor production inhibited the protective effects of chaperone vaccination. These studies provide evidence that chaperone proteins can be isolated from B-cell tumors and used effectively to immunize against disseminated lymphoid malignancies.
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PMID:Immunoprotective activities of multiple chaperone proteins isolated from murine B-cell leukemia/lymphoma. 1074 15

To explore the role of lipid peroxidation (LPO) products in the initial phase of stress mediated signaling, we studied the effect of mild, transient oxidative or heat stress on parameters that regulate the cellular concentration of 4-hydroxynonenal (4-HNE). When K562 cells were exposed to mild heat shock (42 degrees C, 30 min) or oxidative stress (50 microM H2O2, 20 min) and allowed to recover for 2 h, there was a severalfold induction of hGST5.8, which catalyzes the formation of glutathione-4-HNE conjugate (GS-HNE), and RLIP76, which mediates the transport of GS-HNE from cells (Awasthi, S., Cheng, J., Singhal, S. S., Saini, M. K., Pandya, U., Pikula, S., Bandorowicz-Pikula, J., Singh, S. V., Zimniak, P., and Awasthi, Y. C. (2000) Biochemistry 39, 9327-9334). Enhanced LPO was observed in stressed cells, but the major antioxidant enzymes and HSP70 remained unaffected. The stressed cells showed higher GS-HNE-conjugating activity and increased efflux of GS-HNE. Stress-pre-conditioned cells with induced hGST5.8 and RLIP76 acquired resistance to 4-HNE and H2O2-mediated apoptosis by suppressing a sustained activation of c-Jun N-terminal kinase and caspase 3. The protective effect of stress pre-conditioning against apoptosis was abrogated by coating the cells with anti-RLIP76 IgG, which inhibited the efflux of GS-HNE from cells, indicating that the cells acquired resistance to apoptosis by metabolizing and excluding 4-HNE at a higher rate. Induction of hGST5.8 and RLIP76 by mild, transient stress and the resulting resistance of stress-pre-conditioned cells to apoptosis appears to be a general phenomenon since it was not limited to K562 cells but was also evident in lung cancer cells, H-69, H-226, human leukemia cells, HL-60, and human retinal pigmented epithelial cells. These results strongly suggest a role of LPO products, particularly 4-HNE, in the initial phase of stress mediated signaling.
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PMID:Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress. 1152 95

Heat-shock proteins (HSPs) act as molecular chaperones binding endogenous antigenic peptides and transporting them to major histocompatibility complexes. HSPs chaperone a broad repertoire of endogenous peptides including tumor antigens. For the immunotherapy of tumors, a strategy using HSPs may be more advantageous than other procedures because the identification of each tumor-specific antigen is not necessary. In this study, the efficacy of immunotherapy against minimal residual leukemia cells using HSP preparations was evaluated. HSP70 and GP96 were purified from syngeneic leukemia cell line A20 and immunized into BALB/c mice during the reconstitution period of the immune system after syngeneic bone marrow transplantation. In this procedure, all mice not immunized were dead within 60 days of A20 inoculation, whereas the survival times of HSP-immunized mice were significantly prolonged. In addition, the depletion of either CD4(+) or CD8(+) T lymphocyte significantly abrogated this efficacy, indicating that both CD4(+) and CD8(+) T lymphocytes were required for tumor cell rejection. Moreover, the vaccination of HSPs elicited a specific response of potent CD8(+) T lymphocytes cytotoxic against A20 in vitro. These observations suggest that immunization of the complex of HSPs and peptides derived from leukemia cells leads to immune responses. These immune responses are sufficient to reject minimal amounts of leukemia cells for relatively immunocompromised mice after syngeneic bone marrow transplantation.
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PMID:Immunotherapy using heat-shock protein preparations of leukemia cells after syngeneic bone marrow transplantation in mice. 1153 21

Using human acute leukemia HL-60/Bcr-Abl (with ectopic expression of p185 Bcr-Abl) and K562 cells (with endogenous expression of p210 Bcr-Abl) subjected to a continuous selection pressure of up to 1.0 micro M Gleevec (imatinib mesylate, STI-571), we have isolated Gleevec-resistant K562 R (+Bcr-Abl), K562 R (-Bcr-Abl), and HL-60/Bcr-Abl R cells, which display disparate level and activity of Bcr-Abl tyrosine kinase (TK). As compared with their sensitive counterparts, Gleevec-resistant cell types were >/=5-fold resistant to Gleevec-induced apoptosis. Bcr-Abl protein levels were significantly increased in HL-60/Bcr-Abl R and K562 R (+Bcr-Abl) cells, but K562 R (-Bcr-Abl) cells showed a marked decline in the mRNA and protein levels and activity of Bcr-Abl. Bcr-Abl TK level and activity corresponded to the signal transducers and activators of transcription-5 DNA binding activity and up-regulation of heat shock protein 70 levels. The decline in Bcr-Abl expression and TK activity in K562 R (-Bcr-Abl) cells was associated with reduced AKT kinase and signal transducers and activators of transcription-5 DNA binding activities and increased sensitivity to the death ligand Apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand and 1-beta-D-arabinofuranosylcytosine-induced apoptosis. All Gleevec-resistant cell types were sensitive to 17-allylamino-17-demethoxygeldanamycin (17-AAG)- and PD180970 (a SRC and Bcr-Abl TK inhibitor)-induced apoptosis. Treatment with 17-AAG or PD180970 also induced apoptosis of CD34+ leukemic cells from three patients with chronic myeloid leukemia in blast crisis who had progressive leukemia while receiving Gleevec therapy. Taken together, these findings indicate that in addition to overexpression or mutations in Bcr-Abl, resistance to Gleevec may also develop due to a loss of Bcr-Abl expression. These findings also support the rationale to test the in vivo efficacy of 17-AAG and PD180970 against STI-571-resistant Bcr-Abl-positive acute leukemias.
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PMID:Molecular characterization and sensitivity of STI-571 (imatinib mesylate, Gleevec)-resistant, Bcr-Abl-positive, human acute leukemia cells to SRC kinase inhibitor PD180970 and 17-allylamino-17-demethoxygeldanamycin. 1238 36

The linkage of the exposure to the power-line frequency (50-60 Hz) electromagnetic fields (EMF) with human cancers remains controversial after more than 10 years of study. The in vitro studies on the adverse effects of EMF on human cells have not yielded a clear conclusion. In this study, we investigated whether power-line frequency EMF could act as an environmental insult to invoke stress responses in human keratinocytes using the 27-kDa heat shock protein (HSP27) as a stress marker. After exposure to 1 gauss (100 micro T) EMF from 20 min to 24 hr, the isoform pattern of HSP27 in keratinocytes remained unchanged, suggesting that EMF did not induce the phosphorylation of this stress protein. EMF exposure also failed to induce the translocation of HSP27 from the cytoplasm to the nucleus. Moreover, EMF exposure did not increase the abundance of HSP27 in keratinocytes. In addition, we found no evidence that EMF exposure enhanced the level of the 70-kDa heat shock protein (HSP70) in breast or leukemia cells as reported previously. Therefore, in this study we did not detect any of a number of stress responses in human keratinocytes exposed to power-line frequency EMF.
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PMID:Power-line frequency electromagnetic fields do not induce changes in phosphorylation, localization, or expression of the 27-kilodalton heat shock protein in human keratinocytes. 1261 55

Cell membrane localization of the 72 kDa heat shock protein 70 (Hsp70) has been found on different tumour cell lines, on biopsy material from solid tumours and metastases and on leukaemic blasts from acute myelogenous leukaemia patients, but not on the corresponding normal tissues, as determined by flow cytometry using the Hsp70-specific monoclonal antibody C92F3B1. In the present study Hsp70 membrane expression was studied on primary malignant melanomas, melanoma metastases, melanocytes, human skin fibroblasts and peripheral blood lymphocytes, together with expression of the melanoma-associated markers Mel-1, Mel-2 and Mel-5, major histocompatibility complex class I and the fibroblast-specific marker ASO2. As previously shown, fibroblasts and peripheral blood lymphocytes from healthy human volunteers were found to be negative for Hsp70 and for the melanoma-associated markers Mel-1, Mel-2 and Mel-5. Human melanocytes from healthy human donors were also negative for Hsp70, but were positive for Mel-1 and Mel-5. Independent of the Clark's level, all the malignant melanomas (n = 9) and metastases (n = 11) exhibited were positive for both Mel-1 and Mel-2. The primary melanomas could be divided into two groups according to their Hsp70 and Mel-5 expression pattern: those with an Hsp70-negative and a Mel-5-positive phenotype (-/+) (five out of nine), and those with an Hsp70-positive and a Mel-5-negative phenotype (+/-) (four out of nine). All the melanoma metastases (n = 11) had an Hsp70-positive, Mel-5-negative phenotype (+/-). These data provide the first hint that the marker combination Hsp70 positive/Mel-5 negative might be useful in estimating the metastatic potential of a melanoma. Investigations on changes in the marker combination Hsp70/Mel-5 during onset of melanoma disease and progression will clarify its potential as a prognostic risk factor.
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PMID:Heat shock protein 70 membrane expression and melanoma-associated marker phenotype in primary and metastatic melanoma. 1269 Feb 97

To design a specific immunotherapy for leukemia patients, the identification of leukemia-associated antigens (LAAs) is a pivotal step. Antileukemic effects after hematopoetic stem cell transplantation for myeloid leukemias are observed and might be related to the recognition of LAAs. Using the serological screening of an expression library (SEREX) of K562 cells, we identified 16 different clones encoding LAAs eliciting a humoral immune response, among them the heat shock proteins HSJ2 and HSP70, the M-phase phosphoprotein 11 (MPP11), the BRCA1-associated protein (BRAP), the Jkappa recombination binding protein (RBPJkappa) and the receptor for hyaluronic acid mediated motility (RHAMM). Serological responses to MPP11 were observed in 7/19 (37%) of patients with acute myeloid leukemia (AML) and 6/16 (38%) of patients with chronic myeloid leukemia (CML), but not in healthy volunteers (0/20). IgG antibodies directed against MPP11 were also detected in 25-50% of the sera of patients with solid tumors such as melanoma, renal cell, ovarian and breast carcinoma. mRNA expression of MPP11 was detected in 20/20 AML patients and 7/10 patients with CML. In normal tissues, strong mRNA expression of MPP11 was only detected in testis. By real-time PCR, we detected upregulation of MPP11 in leukemic blasts. Simultaneous humoral immune responses to 2 or more of the 16 LAAs identified here was observed, suggesting the feasibility of a polyvalent vaccination as an option for immunotherapies in leukemia patients.
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PMID:Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia. 1280 Jan 98

5-Aminolaevulinic acid-based photodynamic therapy (ALA-PDT) is used to eliminate cancerous cells through photoactivation of endogenously formed protoporphyrin IX (PPIX) following the administration of PPIX precursor, 5-aminolaevulinic acid (ALA). We report on the kinetics of PPIX accumulation and the mechanism of cytotoxic effects of ALA-PDT studied in the chronic myelogenous leukaemia derived cell line K562. The PPIX distribution and, consequently, cytotoxic effects were found to be heterogenous. A subpopulation of K562 cells accumulating PPIX to a lesser extent exhibits only transient cell cycle arrest. A fraction of cells, probably those with higher PPIX accumulation, are irreversibly damaged by ALA-PDT. We detected several signs of an early apoptosis: lowering of Bcl-xL expression, decrease of the mitochondrial and plasma membrane potential, the cytochrome c release into the cytoplasm, and the unmasking of the mitochondrial antigen 7A6. However, late apoptotic events were lacking: neither caspase-3 activation nor DNA fragmentation occurred. Instead, rapidly progressing cell necrosis resulting from plasma membrane damage was observed. We suggest that the high level of the antiapoptotic heat-shock proteins HSP70 and HSP27 found by us in the K562 cells is responsible for the inhibition of the apoptotic process upstream of caspases activation.
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PMID:Early apoptotic features of K562 cell death induced by 5-aminolaevulinic acid-based photodynamic therapy. 1473 53

BACKGROUND: Chaperones (CH) play an important role in tumor biology but no systematic work on expressional patterns has been reported so far. The aim of the study was therefore to present an analytical method for the concomitant determination of several CH in human tumor cell lines, to generate expressional patterns in the individual cell lines and to search for tumor and non-tumor cell line specific CH expression.Human tumor cell lines of neuroblastoma, colorectal and adenocarcinoma of the ovary, osteosarcoma, rhabdomyosarcoma, malignant melanoma, lung, cervical and breast cancer, promyelocytic leukaemia were homogenised, proteins were separated on two-dimensional gel electrophoresis with in-gel digestion of proteins and MALDI-TOF/TOF analysis was carried out for the identification of CH. RESULTS: A series of CH was identified including the main CH groups as HSP90/HATPas_C, HSP70, Cpn60_TCP1, DnaJ, Thioredoxin, TPR, Pro_isomerase, HSP20, ERP29_C, KE2, Prefoldin, DUF704, BAG, GrpE and DcpS. CONCLUSIONS: The ten individual tumor cell lines showed different expression patterns, which are important for the design of CH studies in tumor cell lines. The results can serve as a reference map and form the basis of a concomitant determination of CH by a protein chemical rather than an immunochemical method, independent of antibody availability or specificity.
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PMID:Expressional patterns of chaperones in ten human tumor cell lines. 1559 46

The immune system plays an important role in the treatment of chronic myeloid leukemia (CML). Identification of leukemia-associated antigens (LAAs) eliciting an immune response in patients is a prerequisite for specific immunotherapy of CML. To identify new LAAs in CML, We utilized a novel approach based serology and proteomics technologies. LAAs were identified by comparing the reactivity of proteins resolved by 2-DE with sera from CML patients and healthy donors. Several new LAAs were identified including alpha enolase, aldolase A, HSP70 protein8, beta-tubulin and tropomyosin isoforms. Although, the functions of these identified proteins in CML need further investigation, the detection of autoantibodies in CML may have value on CML screening, diagnosis, or follow-up. Additionally, identification of LAAs in CML may also be of vital importance in antigen-based immunotherapy.
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PMID:Identification of leukemia-associated antigens in chronic myeloid leukemia by proteomic analysis. 1593 17


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