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Background Cytarabine (ara-C) is the major drug for the treatment of acute myeloid leukemia (AML), but cellular resistance to ara-C is a major obstacle to therapeutic success. The present study examined enhanced anti-apoptosis identified in 3 newly established nucleoside analogue-resistant leukemic cell line variants and approaches to overcoming this resistance. Methods HL-60 human AML cells were used to develop the ara-C– or clofarabine (CAFdA)-resistant variants. The Bcl-2 inhibitor venetoclax and the Mcl-1 inhibitor alvocidib were tested to determine whether they could reverse these cells’ resistance. Results A 10-fold ara-C-resistant HL-60 variant, a 4-fold CAFdA-resistant HL-60 variant, and a 30-fold CAFdA-resistant HL-60 variant were newly established. The variants demonstrated reduced deoxycytidine kinase and deoxyguanosine kinase expression, but intact expression of surface transporters (hENT1, hENT2, hCNT3). The variants exhibited lower expression of intracellular nucleoside analogue triphosphates compared with non-variant HL-60 cells. The variants also overexpressed Bcl-2 and Mcl-1. Venetoclax as a single agent was not cytotoxic to the resistant variants. Nevertheless, venetoclax with nucleoside analogs demonstrated synergistic cytotoxicity against the variants. Alvocidib as a single agent was cytotoxic to the cells. However, alvocidib induced G1 arrest and suppressed the cytotoxicity of the co-administered nucleoside analogs. Conclusions Three new nucleoside analogue-resistant HL-60 cell variants exhibited reduced production of intracellular analogue triphosphates and enhanced Bcl-2 and Mcl-1 expressions. Venetoclax combined with nucleoside analogs showed synergistic anti-leukemic effects and overcame the drug resistance.

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Objective We retrospectively compared the clinical efficacy and toxicity of rituximab (R)-THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) with that of R-CHOP (rituximab, adriamicin, cyclophosphamide, vincristine, and prednisolone) in previously untreated old patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients admitted to our institution between 2004 and 2013 were examined. The patients received either R(375 mg/m2, day 1)-THP-COP (pirarubicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5) or R-CHOP (adriamicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5). The doses of chemotherapeutic agents were adjusted depending on the patient's age and associated complications. The treatment was performed for 6 to 8 cycles. Results Among 74 patients with DLBCL (median 76, range 65-90 years; male 39, female 35), 29 received R-THP-COP, while 45 received R-CHOP. The overall response rates were 94.6% (complete response 86.4%, partial response 8.1%). The 2-year overall and progression-free survival rates were 77.6% and 68.5% for the R-THP-COP regimen and 79.2% and 78.9% for R-CHOP, respectively. No significant differences were found between these two regimens regarding the clinical efficacies. The most frequent adverse event was neutropenia (72.4% for the R-THP-COP regimen, 88.9% for the R-CHOP regimen). The cardiac function as evaluated by ejection fraction values was not impaired in either regimen. Conclusion R-THP-COP was effective and safe as an alternative to R-CHOP.

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