摘要:

Nucleotide excision repair (NER) is a multi-enzyme DNA repair pathway in eukaryotes. Several NER genes in this pathway including XPB, XPD, XPA and ERCC-1 have been implicated in anticancer drug resistance in human tumor cells. In this study, we assessed the levels of the above-mentioned proteins in the NCI panel of 60 human tumor cell lines in relation to the cytotoxicity patterns of 170 compounds that constitute the standard agent (SA) database. The database consists of drugs used in the clinic for which a mechanism of action has been at least partially defined. The ERCC-1, XPD and XPB protein expression patterns yielded significant negative Pearson correlations with 13, 32 and 17 out of the 170 compounds, respectively (usingp<0.05). XPA produced a random assortment of negative and positive correlations, and did not appear to confer an overall resistance or sensitivity to these drugs. Protein expression was also compared with a pre-defined categorization of the standard agents into six mechanism-of-action groups resulting in an inverse association between XPD and alkylating agent sensitivity. Our present data demonstrate that XPD protein levels correlate with resistance to alkylating agents in human tumor cell lines suggesting that XPD is implicated in the development of this resistance. NER activity, using thein vitrocell-free system repair assay, revealed no correlation between NER activity and the level of XPD protein in four cell lines with widely varying XPD protein levels. This lack of correlation may be due to the contribution of XPD to other functions including interactions with the Rad51 repair pathway.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Tamoxifen (TAM) is a well-tolerated compound in the treatment of breast cancer and is primarily considered to act by competition with estrogen receptors (ER). Here we investigated thein vitroefficacy and potentially underlying mechanisms of TAM in established cell lines of squamous cell carcinomas of the head and neck (SCCHN). Using proliferation and apoptosis assays the antitumor activity of TAM in five SCCHN and the breast carcinoma line MCF-7 (positive control) was determined. MCF-7 was more sensitive to low-dose TAM (below 1 μM), whereas SCCHN showed significant growth inhibition at higher TAM concentrations (5–10 μM). Growth curve analysis and apoptosis assays were indicative for a cytostatic effect of low-dose TAM and high-dose TAM led to cell loss by apoptosis in sensitive SCCHN. In order to further characterize the observed antitumor effects we determined the amount of steroid hormone receptors with the dextran-coated charcoal method and immunocytochemistry. In addition, production of transforming growth factor (TGF-)-&agr;, -&bgr;1 and -&bgr;2 was measured by ELISA, and protein kinase C (PKC) activity was assessed with a radioligand assay. Except MCF-7, none of the SCCHN lines was positive for ER. TAM caused decreased TGF-&agr;and increased TGF-&bgr;levels in MCF-7, but not in SCCHN supernatants. Furthermore, the antiestrogen reduced PKC activity in MCF-7, but not in SCCHN. In the presentin vitrosystem, the observed antitumor activity of high-dose TAM in SCCHN cannot be explained by estrogen antagonism, alterations of TGF-&agr;/&bgr;levels or decreased PKC activity.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The effect ofN-1-(3,5-dimethyladamantyl)maleimide (DMAMI) on the growth of Colo205 human colon cancer cells was examined bothin vitroandin vivo. Flow cytometry analysis showed a decrease of G2/M Colo205 cells at 4–6 h after treatment with DMAMI prior to accumulation of apoptotic cells at 24 h. Significant changes in cell morphology, i.e. shrinkage and chromatin condensation of cells, were observed after treatment with DMAMI. In the analysis of the apoptosis markers, it was found that the increase of Annexin V binding to membrane, peroxide radicals, dissipation of the mitochondrial membrane potential, and the activation of caspase-3, -8 and -9 were all evident at 4–6 h after treatment with DMAMI.In vivoanalysis showed that treatment of Colo205 tumor-bearing SCID mice with DMAMI (230 mg/kg, intratumoral, once) resulted in rapid tumor damage that leads to significant tumor growth inhibition and no obvious acute toxicity. These results suggest that DMAMI has potential for local treatment of cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID