title: High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects.
abstract: We document for the first time that sanctuary in an organ which expresses high levels of the enzyme cytidine deaminase (CDA) is a mechanism of cancer cell resistance to cytidine analogues. This mechanism could explain why historically, cytidine analogues have not been successful chemotherapeutics against hepatotropic cancers, despite efficacy in vitro. Importantly, this mechanism of resistance can be readily reversed, without increasing toxicity to sensitive organs, by combining a cytidine analogue with an inhibitor of cytidine deaminase (tetrahydrouridine). Specifically, CDA rapidly metabolizes cytidine analogues into inactive uridine counterparts. Hence, to determine if sheltering/protection of cancer cells in organs which express high levels of CDA (e.g., liver) is a mechanism of resistance, we utilized a murine xenotransplant model of myeloid cancer that is sensitive to epigenetic therapeutic effects of the cytidine analogue decitabine in vitro and hepato-tropic in vivo. Treatment of tumor-bearing mice with decitabine (subcutaneous 0.2mg/kg 2X/week) doubled median survival and significantly decreased extra-hepatic tumor burden, but hepatic tumor burden remained substantial, to which the animals eventually succumbed. Combining a clinically-relevant inhibitor of CDA (tetrahydrouridine) with a lower dose of decitabine (subcutaneous 0.1mg/kg 2X/week) markedly decreased liver tumor burden without blood count or bone marrow evidence of myelotoxicity, and with further improvement in survival. In conclusion, sanctuary in a CDA-rich organ is a mechanism by which otherwise susceptible cancer cells can resist the effects of decitabine epigenetic therapy. This protection can be reversed without increasing myelotoxicity by combining tetrahydrouridine with a lower dose of decitabine.
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Quteba
authors.initials: Q
authors.lastname: Ebrahem
authors.forename: Reda Z
authors.initials: RZ
authors.lastname: Mahfouz
authors.forename: Kwok Peng
authors.initials: KP
authors.lastname: Ng
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003564:Cytidine Deaminase / Q000378:metabolism*; D000077209:Decitabine; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013767:Tetrahydrouridine / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D013767:Tetrahydrouridine; D000077209:Decitabine; D003564:Cytidine Deaminase; D001374:Azacitidine