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dc.contributor.authorSutherland, Mark*
dc.contributor.authorGill, Jason H.*
dc.contributor.authorLoadman, Paul*
dc.contributor.authorLaye, Jonathan P.*
dc.contributor.authorSheldrake, Helen M.*
dc.contributor.authorIllingworth, Nicola A.*
dc.contributor.authorAlandas, Mohammed N.*
dc.contributor.authorCooper, Patricia A.*
dc.contributor.authorSearcey, M.*
dc.contributor.authorPors, Klaus*
dc.contributor.authorShnyder, Steven*
dc.contributor.authorPatterson, Laurence H.*
dc.date.accessioned2014-04-28T11:21:25Z
dc.date.available2014-04-28T11:21:25Z
dc.date.issued2013-01
dc.identifier.citationSutherland M, Gill JH, Loadman PM et al (2013) Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder. Molecular Cancer Therapeutics. 12(1): 27-37.
dc.identifier.urihttp://hdl.handle.net/10454/6210
dc.descriptionNoen
dc.description.abstractWe identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.
dc.subjectAnimals
dc.subjectAntineoplastic agents
dc.subjectBiotransformation
dc.subjectCHO cells
dc.subjectCarcinoma
dc.subjectCell line; Tumor
dc.subjectCell survival
dc.subjectCricetinae
dc.subjectCytochrome P-450 CYP1A1
dc.subjectFemale
dc.subjectGene expression
dc.subjectHumans
dc.subjectIndoles
dc.subjectLiver
dc.subjectMaximum tolerated dose
dc.subjectMice
dc.subjectInbred BALB C
dc.subjectMicrosomes
dc.subjectPyrroles
dc.subjectTumor burden
dc.subjectUrinary bladder neoplasms
dc.subjectXenograft model antitumor assays
dc.subjectREF 2014
dc.subjectMetabolism
dc.subjectPharmacokinetics
dc.subjectPharmacology
dc.subjectTransitional cell
dc.subjectDrug therapy
dc.subjectEnzymology
dc.subjectPathology
dc.subjectGenetics
dc.titleAntitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder
dc.status.refereedYesen
dc.date.Accepted2012-09-24
dc.date.application2012-10-01
dc.typeArticle
dc.type.versionNo full-text in the repositoryen
dc.identifier.doihttps://doi.org/10.1158/1535-7163.MCT-12-0405


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