Research Article: Bone Marrow and Peripheral Blood AML Cells Are Highly Sensitive to CNDAC, the Active Form of Sapacitabine

Date Published: September 23, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Sucheta Jagan, Laura A. Paganessi, Robin R. Frank, Parameswaran Venugopal, Melissa Larson, Kent W. Christopherson.

http://doi.org/10.1155/2012/727683

Abstract

Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated the in vitro efficacy of the active form of novel agent sapacitabine, CNDAC, compared to current chemotherapeutic drugs Ara-C and mitoxantrone using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from AML patients. Cell lines were exposed to compound for 3–6 days and primary cells for 4 days. The viability of primary cells was additionally evaluated 3, 7, and 31 days after removal of tested compound to determine the durability of the response. Our studies indicate that CNDAC and mitoxantrone have a greater impact on viability than ara-C in primary AML cells and AML cell lines. CNDAC is more effective at reducing viability and inducing apoptosis than ara-C at equivalent concentrations in the THP-1 cell line, which is defined as displaying resistance to ara-C. As sapacitabine has shown in vivo activity at clinically achievable doses, future studies are warranted to assess the potential for combining it with ara-C and/or mitoxantrone, with an emphasis on cells and patients insensitive to ara-C treatment.

Partial Text

Acute myeloid leukemia (AML) therapy is continually challenged by high incidences of disease relapse and patient mortality. The overall 5-year survival rate for AML is 30–40% for patients >45 years and <10% for patients over 60 years [1]. However, the long-term event free survival rate of these patients is only 20–50% [2, 3]. The current AML therapy, “7 + 3” regimen with cytarabine (ara-C) and an anthracycline such as daunorubicin, idarubicin, or the synthetic anthracenedione mitoxantrone, has been the standard of care for decades. The nucleoside analog ara-C forms the backbone of AML treatment, either in low doses during induction therapy, or at high doses for maintenance after remission [4, 5]. Although high dose therapy has been shown to improve survival, 60–70% of patients relapse and eventually die due to disease progression [4, 6]. Moreover, there are patients who are nonresponsive to ara-C and many elderly AML patients cannot tolerate the regime and hence are not eligible for intensive chemotherapy. Novel therapeutic approaches are therefore required. This study compared the cytotoxic effects of novel agent CNDAC to conventional agents, ara-C and mitoxantrone. The activity of ara-C and CNDAC is cell cycle dependent. Cell lines plated at low seeding densities have higher proliferation rates indicative of actively dividing cells thereby lowering IC50's of the drugs. Conversely, at high seeding densities, cells have lower proliferation rates thus requiring higher doses of drug to achieve similar effects (Table 2). Regardless of seeding densities, HL-60 cells were more sensitive to CNDAC than ara-C. Significant cell death is induced by CNDAC at low doses (0.5 μM), indicating that higher doses are unnecessary. A low effective dose is highly desired in the clinical setting, as low doses usually equate to less toxicity and meylosuppression in patients.   Source: http://doi.org/10.1155/2012/727683

 

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