Global ETD Search

11	Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins Travica, S., Pors, Klaus, Loadman, Paul, Shnyder, Steven, Johansson, I., Alandas, Mohammed N., Sheldrake, Helen M., Mkrtchian, S., Patterson, Laurence H., Ingelman-Sundberg, M. January 2013 (has links) No / PURPOSE: 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. Animals Bystander effect Cell line Colonic neoplasms Cytochrome P-450 enzyme system Cytotoxins DNA damage Drug resistance Female Gene expression Heterocyclic compounds Humans Indoles Mice Tissue distribution Tumor burden Xenograft model antitumor assays REF 2014 Tumor 3-Ring Neoplasm Drug effects Pharmacokinetics Toxicity Metabolism Enzymology Genetics Pathology
12	The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53 Thomas, A., Perry, T., Berhane, S., Oldreive, C., Zlatanou, A., Williams, L.R., Weston, V.J., Stankovic, T., Kearns, P., Pors, Klaus, Grand, R.J., Stewart, G.S. 06 January 2015 (has links) Yes / Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes. Animals Anthraquinones Antigens Antineoplastic agents Ataxia telangiectasia mutated proteins Cell death Cell line DNA damage DNA repair DNA replication DNA topoisomerases DNA-Binding proteins Dose-response relationship G2 phase cell cycle checkpoints Humans Leukemia M phase cell cycle checkpoints Mice Topoisomerase inhibitors Tumor suppressor protein p53 Xenograft model antitumor assays

Search results

Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53