tetrahydrouridine and Leukemia--Myeloid

Topics: Bone Marrow; Cytarabine; DNA, Neoplasm; Drug Therapy, Combination; Female; Humans; In Vitro Techniques; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; RNA, Neoplasm; Tetrahydrouridine; Thymidine

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.

Topics: Animals; Antimetabolites; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cytidine Deaminase; Decitabine; Humans; Leukemia, Myeloid; Liver; Liver Neoplasms; Mice; Mice, Knockout; Tetrahydrouridine; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m2 in three patients, 1,200 mg/m2 in five patients), tetrahydrouridine (THU: 2,800 mg/m2 in two patients, 2,646 mg/m2 in one patient, 2,100 mg/m2 in five patients), and carboplatin (900 mg/m2 in four patients, 720 mg/m2 in one patient, 450 mg/m2 in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630 +/- 1170 ng/ml).

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Carboplatin; Cytarabine; Drug Resistance; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Middle Aged; Recurrence; Tetrahydrouridine; Treatment Outcome

Topics: Bone Marrow; Cells, Cultured; Cytarabine; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Phosphotransferases; Tetrahydrouridine; Uridine

Topics: Bone Marrow; Bone Marrow Cells; Cytarabine; Cytidine Deaminase; Deoxycytidine; Drug Resistance; Erythrocytes; Granulocytes; Humans; Kinetics; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Nucleoside Deaminases; Phosphotransferases; Tetrahydrouridine