title: Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden. sandra.travica@ki.se
authors.forename: Sandra
authors.initials: S
authors.lastname: Travica
authors.forename: Klaus
authors.initials: K
authors.lastname: Pors
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.forename: Inger
authors.initials: I
authors.lastname: Johansson
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Alandas
authors.forename: Helen M
authors.initials: HM
authors.lastname: Sheldrake
authors.forename: Souren
authors.initials: S
authors.lastname: Mkrtchian
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Patterson
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
mesh_terms: D000818:Animals; D024201:Bystander Effect; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003603:Cytotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D007211:Indoles / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C585469:(1-(chloromethyl)-1,2-dihydropyrrolo(3,2-e)indol-3(6H)-yl)(5-fluoro-1H-indol-2-yl)methanone; C585470:(5-chloro-1H-indol-2-yl)(1-(chloromethyl)-1,2-dihydropyrrolo(3,2-e)indol-3(6H)-yl)methanone; D003603:Cytotoxins; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D003577:Cytochrome P-450 Enzyme System; C509336:CYP2W1 protein, human; D000072467:Cytochrome P450 Family 2