Abstract | PURPOSE: 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.
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Authors | Sandra Travica, Klaus Pors, Paul M Loadman, Steven D Shnyder, Inger Johansson, Mohammed N Alandas, Helen M Sheldrake, Souren Mkrtchian, Laurence H Patterson, Magnus Ingelman-Sundberg |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 19
Issue 11
Pg. 2952-61
(Jun 01 2013)
ISSN: 1557-3265 [Electronic] United States |
PMID | 23589180
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2013 AACR |
Chemical References |
- (1-(chloromethyl)-1,2-dihydropyrrolo(3,2-e)indol-3(6H)-yl)(5-fluoro-1H-indol-2-yl)methanone
- (5-chloro-1H-indol-2-yl)(1-(chloromethyl)-1,2-dihydropyrrolo(3,2-e)indol-3(6H)-yl)methanone
- Cytotoxins
- Heterocyclic Compounds, 3-Ring
- Indoles
- Cytochrome P-450 Enzyme System
- CYP2W1 protein, human
- Cytochrome P450 Family 2
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Topics |
- Animals
- Bystander Effect
- Cell Line, Tumor
- Colonic Neoplasms
(enzymology, genetics, pathology)
- Cytochrome P-450 Enzyme System
(metabolism)
- Cytochrome P450 Family 2
- Cytotoxins
(pharmacokinetics, toxicity)
- DNA Damage
(drug effects)
- Drug Resistance, Neoplasm
(genetics)
- Female
- Gene Expression
- Heterocyclic Compounds, 3-Ring
(metabolism, pharmacokinetics, toxicity)
- Humans
- Indoles
(metabolism, pharmacokinetics, toxicity)
- Mice
- Tissue Distribution
- Tumor Burden
(drug effects)
- Xenograft Model Antitumor Assays
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