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.