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The sensitivity of human tumour cells to quinone-based bioreductive anticancer agents
Başlık:
The sensitivity of human tumour cells to quinone-based bioreductive anticancer agents
Yazar:
Robertson, Naomi, author.
ISBN:
9780438043213
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (353 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Bioreductive drugs require reductive activation in order to yield toxic metabolites capable of killing tumour cells. This can occur in hypoxic cells, and also requires that cells possess the appropriate reductase enzymes for the activation process. This study has focused on one class of bioreductive anticancer agents, the quinones, and has examined the factors that influence the in vitro toxicity of several of these agents towards human tumour cells. Twenty-three human tumour cell lines (lung, breast and colon) were evaluated for their sensitivity, using the MTT assay, to mitomycin C, its disulphide derivative BMY 25067 and the indolequinone E09. Sensitivity varied 1000-fold within this cell line panel, and BMY 25067 and E09 demonstrated increased potency compared to mitomycin C. The obligate two-electron reductase DT-diaphorase is an attractive target for bioreductive drug development, as elevated levels of this enzyme have been reported in several tmnour types compared to normal tissues. Quinone drug sensitivity was compared with intracellular levels of DT-diaphorase, and a relationship was found between high enzyme activity and cellular sensitivity to E09 (no relationship was evident for mitomycin C or BMY 25067). Experiments carried out under hypoxia reveal the potential contribution of one- electron reductive activation to subsequent toxicity, as these reactions may be reversible in oxygen. Hypoxia greatly increased E09 cytotoxicity in cells containing low, but not high levels of DT-diaphorase, implying that both one- and two-electron reductive activation processes can be important for expression of E09 toxicity. Structure activity relationships for the indolequinones have been confirmed in human tumour cells using analogues of E09. The finding that cells become more resistant to BMY 25067 under hypoxia suggests that oxygen radical formation could be a major contributer to the toxicity of this drug. Glutathione (GSH) can activate BMY 25067, and we have demonstrated a strong correlation between high intracellular GSH levels and BMY 25067 sensitivity in non-small cell lung cancer (NSCLC) cell lines. A similar relationship is evident for mitomycin C, in contrast to the generally held view that GSH detoxifies this drug. In addition, a potential relationship between glutathione S transferase (GST) pi and increased sensitivity to BMY 25067 suggests that this drug may be useful for drug resistant tumours or tumours expressing high levels of GSTpi. Further studies were carried out using three NSCLC cell lines, which exhibited a wide range in sensitivity to mitomycin C in air despite possessing similar levels of reductive enzymes. DNA damage after mitomycin C exposure was found to be similar. Cell cycle analysis revealed that mitomycin C was inducing arrest at the G2 phase for different durations, however, these differences could not be related to the relative sensitivities of the cell lines. In order to interpret these results, mitomycin C sensitivity was determined using several different assays, and apoptosis induction was also examined. The clonogenic (colony-forming) assay showed the cell lines to have very similar sensitivities to mitomycin C (in agreement with the levels of reductive enzymes and DNA damage formed), and appeared to most accurately reflect the sensitivity of these cell lines to this drug. The MTT and sulforhodamine B (SRB) assays were susceptible to drug-induced alterations in mitochondrial function and cell size. No differences were seen in the cell lines regarding induction of apoptosis after mitomycin C exposure. In conclusion, this study formed part of an 'enzyme-directed approach' to bioreductive drug development. A large variation in response of human tumour cells to quinone-based bioreductive agents has been demonstrated, and some of the biochemical factors underlying the differences in sensitivity have been revealed. Such information will be important for the design of improved analogues of these compounds, and provide a rational framework for the clinical application of these agents.
Notlar:
School code: 1543
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684258.1) | 684258-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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