Show simple item record

dc.contributor.authorTravica, S.*
dc.contributor.authorPors, Klaus*
dc.contributor.authorLoadman, Paul*
dc.contributor.authorShnyder, Steven*
dc.contributor.authorJohansson, I.*
dc.contributor.authorAlandas, Mohammed N.*
dc.contributor.authorSheldrake, Helen M.*
dc.contributor.authorMkrtchian, S.*
dc.contributor.authorPatterson, Laurence H.*
dc.contributor.authorIngelman-Sundberg, M.*
dc.date.accessioned2014-04-28T11:27:04Z
dc.date.available2014-04-28T11:27:04Z
dc.date.issued2013
dc.identifier.citationTravica S, Pors K, Loadman PM et al (2013) Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins. Clinical Cancer Research. 19(11): 2952-2961.
dc.identifier.urihttp://hdl.handle.net/10454/6217
dc.descriptionNo
dc.description.abstractPURPOSE: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents. EXPERIMENTAL DESIGN: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts. RESULTS: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue. CONCLUSION: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1.
dc.language.isoen
dc.subjectAnimals
dc.subjectBystander effect
dc.subjectCell line
dc.subjectColonic neoplasms
dc.subjectCytochrome P-450 enzyme system
dc.subjectCytotoxins
dc.subjectDNA damage
dc.subjectDrug resistance
dc.subjectFemale
dc.subjectGene expression
dc.subjectHeterocyclic compounds
dc.subjectHumans
dc.subjectIndoles
dc.subjectMice
dc.subjectTissue distribution
dc.subjectTumor burden
dc.subjectXenograft model antitumor assays
dc.subjectREF 2014
dc.subjectTumor
dc.subject3-Ring
dc.subjectNeoplasm
dc.subjectDrug effects
dc.subjectPharmacokinetics
dc.subjectToxicity
dc.subjectMetabolism
dc.subjectEnzymology
dc.subjectGenetics
dc.subjectPathology
dc.titleColon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins
dc.typeArticle
dc.type.versionNo full-text in the repository
dc.identifier.doihttps://doi.org/10.1158/1078-0432.CCR-13-0238
dc.openaccess.statusclosedAccess


This item appears in the following Collection(s)

Show simple item record