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.
Highlights
Cytidine analogue chemotherapeutics are rapidly metabolized into inactive uridine counterparts by the enzyme cytidine deaminase (CDA)[1,2,3,4]
The myeloid cancer cell line THP1 was used for these experiments, since we have demonstrated its sensitivity to non-cytotoxic, DNA methyl-transferase 1 (DNMT1)-depleting concentrations of decitabine in vitro, and its hepatotropism in vivo[26]
Malignant cells find sanctuary from decitabine in the liver: Mice were inoculated by tail-vein injection with 0.4x106 THP1 myeloid cancer cells, which are sensitive to non-cytotoxic, DNMT1 depleting concentrations of decitabine in vitro and hepatotropic in vivo[26]
Summary
Cytidine analogue chemotherapeutics are rapidly metabolized into inactive uridine counterparts by the enzyme cytidine deaminase (CDA)[1,2,3,4]. It is possible that high expression of CDA in some organs, such as the liver, provides protection for malignant cells from the effects of cytidine analogues. Such protection or sanctuary has not been formally evaluated as an actual mechanism of resistance to cytidine analogues, and there are no routine measures in place to reverse it, even though it could explain the historically poor responses of hepatotropic cancers treated with cytidine analogues[9,10]. In contrast to the cytidine analogues cytarabine and gemcitabine, which are administered at high dosage (100-3000 mg/m2) derived from maximum tolerated levels and intended for anti-metabolite cytotoxic effects, 5-azacytidine and decitabine are administered at relatively www.impactjournals.com/oncotarget
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