Abstract:
:The substituted phenazines XR11576 and XR5944 were originally described as dual topoisomerase-I/II poisons. Subsequent reports, however, indicated that the association of their cytotoxicity with cellular topoisomerases was not clear. We set out to study this further using human tumour cell lines, PEO1 ovarian cancer, MDA-MB-231 breast cancer and variants with acquired resistance to VP-16 and XR11576: PEO1VPR, MB-231VPR, MB-231-11576R and camptothecin: PEO1CamR. Cytotoxicity testing [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay], DNA-protein crosslink formation, cell cycle analysis (flow cytometry) for DNA content, apoptosis (flow cytometry) for Annexin V and Western blotting for apoptotic factors. Cytotoxicity testing showed potent cytotoxicity with no cross-resistance to XR11576 or XR5944 in VP-16 or camptothecin-resistant lines. Importantly, we have shown for the first time that the activities of XR5944 and XR11576 are similar as MB-231-11576R cells were resistant to both agents and to a similar extent. XR5944 showed the greatest, albeit slower, interaction with DNA with high levels of DNA-protein crosslinks. Levels of apoptosis in XR5944-treated cells were significantly less than those in VP-16 or XR11576 treatments, suggestive of a more cytostatic rather than cytotoxic mode of action. Interestingly, XR5944 failed to give rise to a G2/M blockade, in contrast to VP-16 or XR11576. XR5944 and XR11576, in line with a dual topoisomerase-I/II-directed mechanism of action, retain potent activity in tumour cells with acquired resistance to VP-16 and camptothecin. Although these agents appear to behave differently from each other according to experimental conditions, this study suggests a substantial overlap in their mechanism(s) of action.
journal_name
Anticancer Drugsjournal_title
Anti-cancer drugsauthors
Lewis LJ,Mistry P,Charlton PA,Thomas H,Coley HMdoi
10.1097/CAD.0b013e328010772fsubject
Has Abstractpub_date
2007-02-01 00:00:00pages
139-48issue
2eissn
0959-4973issn
1473-5741pii
00001813-200702000-00005journal_volume
18pub_type
杂志文章abstract::Large (>6 microm) rigid microparticles (MPs) become passively entrapped within the lungs after intravenous (i.v.) injection making them an attractive and highly efficient alternative to inhalation for pulmonary delivery. In this study, PEGylated 6 microm polystyrene MPs with multiple copies of the norvaline (Nva) alph...
journal_title:Anti-cancer drugs
pub_type: 杂志文章
doi:10.1097/CAD.0b013e328332a322
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
pub_type: 杂志文章
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journal_title:Anti-cancer drugs
pub_type: 杂志文章
doi:10.1097/00001813-199402000-00008
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
pub_type: 临床试验,杂志文章
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journal_title:Anti-cancer drugs
pub_type: 杂志文章
doi:10.1097/CAD.0000000000000635
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
pub_type: 杂志文章
doi:10.1097/00001813-199909000-00011
更新日期:1999-09-01 00:00:00
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journal_title:Anti-cancer drugs
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1097/00001813-199701000-00005
更新日期:1997-01-01 00:00:00
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journal_title:Anti-cancer drugs
pub_type: 杂志文章
doi:10.1097/00001813-199903000-00012
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pub_type: 杂志文章,随机对照试验
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
pub_type: 杂志文章
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journal_title:Anti-cancer drugs
pub_type: 临床试验,杂志文章,多中心研究
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journal_title:Anti-cancer drugs
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journal_title:Anti-cancer drugs
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