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  • 1
    Electronic Resource
    Electronic Resource
    Geldanamycin-induced cytotoxicity in human colon-cancer cell lines: evidence against the involvement of c-Src or DT-diaphorase (1998)
    Springer
    Cancer chemotherapy and pharmacology 41 (1998), S. 417-422 
    Details
    ISSN: 1432-0843
    Keywords: Key words Geldanamycin ; Colon cancer ; c-Src ; DT-diaphorase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We investigated two of the major proposed modes of action of the benzoquinoid ansamycin geldanamycin using a pair of human colon-carcinoma cell lines, BE and HT29. One potential mechanism of action in colorectal cancer is the inhibition of c-Src kinase activity, since this proto-oncogene is hyperexpressed in human large-bowel tumours. Our results show that despite the 9-fold higher level of c-Src kinase activity found in HT29 cells, there was only a 1.4-fold difference in cytotoxicity as compared with BE cells, the latter being the most sensitive. Moreover, even at concentrations of geldanamycin that resulted in cell kill of 80% or more after a 24-h period of exposure, there was no effect on␣␣␣ c-Src kinase activity in HT29 cells, although c-Src protein was depleted at supralethal levels of exposure. We also investigated the metabolism of the quinone moiety of geldanamycin by DT-diaphorase, an enzyme that activates certain quinone antibiotics such as mitomycin C and is hyperexpressed in colorectal cancer cells. Geldanamycin was shown to be a substrate for␣DT-diaphorase present in HT29 cells. However, the lack of a major differential in cytotoxicity between HT29 and BE cells indicates that this is unlikely to be pharmacologically significant, since the former contains high levels of enzyme activity, whereas BE cells have no significant activity due to a point mutation in the DT-diaphorase (NQO1) gene. Although reduction of geldanamycin was also catalysed by non-DT-diaphorase reductases in HT29 and BE cells, providing the potential for free radical induction, this is unlikely to be significant since studies previously reported by us elsewhere showed that cells exposed to geldanamycin exhibited no evidence of DNA damage. Thus, as far as the mode of action of geldanamycin in human colon-carcinoma cells is concerned, the present results rule out two major possibilities, namely, the involvement of c-Src tyrosine kinase inhibition and DT-diaphorase metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050760
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  • 2
    Electronic Resource
    Electronic Resource
    Differential single- versus double-strand DNA breakage produced by doxorubicin and its morpholinyl analogues (1996)
    Springer
    Cancer chemotherapy and pharmacology 38 (1996), S. 210-216 
    Details
    ISSN: 1432-0843
    Keywords: Key words Anthracyclines ; DNA strand breakage ; Morpholinyl doxorubicin ; MX2 ; topoisomerases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The morpholinyl analogues of doxorubicin (DOX) have previously been reported to be non-cross-resistant in multidrug resistant (MDR) cells due to a lower affinity for P-glycoprotein relative to the parent compound. In order to further investigate the mechanisms of action of these morpholinyl anthracyclines, we examined their ability to cause DNA single- and double-strand breaks (SSB, DSB) and their interactions with topoisomerases. Alkaline elution curves were determined after 2-h drug treatment at 0.5, 2 and 5 μM, while neutral elution was conducted at 5, 10 and 25 μM in a human ovarian cell line, ES-2. A pulse-field gel electrophoresis assay was used to confirm the neutral elution data under the same conditions. Further, K-SDS precipitation and topoisomerase drug inhibition assays were used to determine the effects of DOX and the morpholinyl analogues on topoisomerase (Topo) I and II. Under deproteinated elution conditions (pH 12.1), DOX, morpholinyl DOX (MRA), methoxymorpholinyl DOX (MMDX) and morpholinyl oxaunomycin (MX2) were equipotent at causing SSB in the human ovarian carcinoma cell line, ES-2. However, neutral elution (pH 9.6) under deproteinated conditions revealed marked differences in the degree of DNA DSB. After 2-h drug exposures at 10 μM, DSBs were 3300 rad equivalents for MX2, 1500 for DOX and 400 for both MRA and MMDX in the ES-2 cell line. Pulse-field data substantiated these differences in DSBs, with breaks easily detected after MX2 and DOX treatment, but not with MRA and MMDX. DOX and MX2 thus cause DNA strand breaks selectively through interaction with Topo II, but not Topo I. In contrast, MRA and MMDX cause DNA breaks through interactions with both topoisomerases with a predominant inhibition of Topo I.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050473
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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