Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyanoguanidine CHS 828 has shown promising antitumor properties and is currently in early clinical trials, although the mechanism of action still is largely unknown. In this study, resistant sublines of the histiocytic lymphoma cell line U-937 GTB and the myeloma line RPMI 8226 were developed by culturing under gradually increasing concentrations of CHS 828 until reaching 25 times the parental line EC50s. The new phenotypes demonstrate more than 400-fold resistance to CHS 828 and cross-resistance to six cyanoguanidine analogs, but no resistance to nine standard drugs of different mechanistic classes or to the cytotoxic guanidines m-iodobenzylguanidine and methylglyoxal-bis(guanylhydrazone). The resistant phenotypes were stable for several months even if cultivated in drug-free medium and no difference in proliferation, ultrastructural or morphologic appearance in the sublines could be detected. Neither was decreased accumulation of tritium-labeled CHS 828 observed. Furthermore, the new U-937 phenotype was not accompanied by changes in differentiation or an altered cell-cycle distribution. In the myeloma cell line, esterase activity was shown to be moderately enhanced. Two-dimensional protein electrophoresis was undertaken to unmask possible resistance-mediating proteins and/or the target molecule(s) for CHS 828. In the myeloma cell line, lambda light chain immunoglobulin (down-regulated) and a fatty acid-binding protein (up-regulated) were identified. The findings presented here indicate that development of specific cellular alterations is responsible for the gained CHS 828 resistance.
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PMID:Development and characterization of two human tumor sublines expressing high-grade resistance to the cyanoguanidine CHS 828. 1509 Jul 43

CHS 828 is a pyridyl cyanoguanidine with promising antitumor activity both in vitro and in vivo, and has previously been found especially active against tumor cells obtained from patients with B cell chronic lymphocytic leukemia. In the present study the cytotoxic effect in vitro of CHS 828 was investigated on a panel of 10 human myeloma cell lines using the fluorometric microculture cytotoxicity assay. CHS 828 induced a concentration-dependent, but variable decrease in tumor cell survival in the cell line panel with inhibitory concentrations 50% (IC50) in the range 0.01-0.3 microM. These concentrations are below those achievable in vivo. There was no detectable dependence on P-glycoprotein-mediated or GSH-associated drug resistance and the drug showed low to moderate cross-resistance with standard drugs, including melphalan, vincristine and doxorubicin. Furthermore, sensitivity to CHS 828 showed no apparent relationship to growth factor dependence, tumor progression or phenotypic variability. CHS 828 was also tested in vivo using a hollow fiber model in rats with three of the cell lines. The results indicate a high cytotoxic activity of CHS 828. Overall, the results show a high cytotoxic activity of CHS 828 in the myeloma models, which might warrant its further development against myeloma.
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PMID:Cytotoxic effect in vivo and in vitro of CHS 828 on human myeloma cell lines. 1509 Jul 45

CHS is a cutaneous, T cell-dependent, inflammatory reaction mediated mainly by antigen-specific effector T cells. Bortezomib is a proteasome inhibitor that has shown impressive efficacy for the treatment of multiple myeloma. In the current study, we have assessed the effect of bortezomib treatment of CHS in mice and found that bortezomib potently inhibited CHS responses. The attenuation of CHS responses was associated with decreased inflammatory cell infiltration in the challenged skin. Specifically, bortezomib-treated mice showed significantly decreased numbers of CD4(+) and CD8(+) T cells in the challenged skin and draining lymph nodes. Cytoplasmic IFN-gamma production by CD4(+) and CD8(+) T cells in the draining lymph nodes was decreased substantially by bortezomib treatment. Notably, bortezomib enhanced T cell apoptosis by inhibiting NF-kappaB activation during CHS responses. Thus, bortezomib treatment is likely to induce T cell death, thereby suppressing CHS responses by reducing IFN-gamma production. These findings suggest that bortezomib treatment could be a promising strategy for treating autoimmune and inflammatory disease.
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PMID:The proteasome inhibitor bortezomib inhibits T cell-dependent inflammatory responses. 2041 48