SNS-314 is a potent small-molecule inhibitor of Aurora kinases developed as a novel anti-cancer therapeutic agent for the treatment of diverse human malignancies.
Main purposeVoreloxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective DNA damage. Voreloxin is in clinical studies, as a single agent and in combination with cytarabine, for the treatment of acute myeloid leukemia (AML). The preclinical studies reported here were performed to investigate the activity of voreloxin alone and in combination with cytarabine, in support of the clinical program.Research questionsIs single agent voreloxin active in preclinical models of AML? Does the combination of voreloxin and cytarabine enhance the activity of either agent alone?MethodsInhibition of proliferation was studied in three cancer cell lines: HL-60 (acute promyelocytic leukemia), MV4-11 (AML), and CCRF-CEM (Acute lymphoblastic leukemia). Combination index (CI) analysis established the effect of the drugs in combination. A mouse model of bone marrow ablation was used to investigate in vivo efficacy of the drugs alone and in combination. Peripheral white blood cell and platelet counts were followed to assess marrow impact and recovery.ResultsVoreloxin and cytarabine alone and in combination exhibited cytotoxic activity in human leukemia cell lines and in vivo. The two drugs had additive or synergistic activity in vitro and supra-additive activity in vivo. Bone marrow ablation was accompanied by reductions in peripheral white blood cells and platelets that were reversible within 1 week, consistent with the AML treatment paradigm.ConclusionsThese data support ongoing clinical evaluation of voreloxin both alone and in combination with cytarabine for the treatment of AML.
SNS-595 is a novel naphthyridine analog, a class of compounds not previously used for cancer treatment. SNS-595 is currently in an escalating-dose phase 1 trial in acute leukemia and several phase 2 studies in solid tumors. SNS-595 has a unique mechanism of action; causing double-strand breaks during S phase that are solely repaired through a DNA-PK-dependent pathway. This damage induces DNA damage-repair signals through both p53 and p73 pathways during DNA synthesis and is accompanied by a rapid onset of apoptosis and an irreversible G2 arrest. This mechanism suggests that SNS-595 could interact in combination favorably with other DNA damaging agents that utilize different mechanisms of damage signaling and repair. SNS-595 demonstrates potent anti-proliferative effects on human leukemic cell lines in vitro and is active in LM-3 Jck and CCRF-CEM hematologic xenograft models. Previously, we have shown that administration of SNS-595 results in a dose dependent loss in bone marrow cellularity and reduction in circulating neutrophils in mice (Proc. Amer. Assoc. Cancer. Res.47: 4726, 2006). These data suggest that SNS-595 activity in bone marrow and circulating blood may provide a therapeutic rationale for the treatment of acute leukemias and advanced chronic myelogenous leukemia. In this study we evaluated the effects of SNS-595 on peripheral white blood cells and bone marrow cellularity as a single agent and in combination with cytarabine (Ara-C) and daunorubicin (DNR). SNS-595 dosed once a day at 10 mg/kg IV as a single agent and Ara-C dosed three times a day as a single agent at 20 mg/kg SC, on day 0 and 4, resulted in 44% and 12% reductions in cellularity, respectively. In contrast, combination dosing of SNS-595 once a day at 10 mg/kg IV with Ara-C dosed three times a day at 20 mg/kg SC resulted in a 93% reduction in cellularity. Normal cellularity recovered on Day 12 (8 days post last dose). Furthermore, the SNS-595/Ara-C combination reduced cellularity more than Ara-C dosed at the MTD of 60 mg/kg three times a day SC (42% reduction in cellularity). Circulating leukocyte levels were also reduced including neutrophils that dropped from 1359 cells/ml to 587 cells/ml for SNS-595 dosed at 10 mg/kg IV and 1212 cells/ml for Ara-C dosed three times a day at 20 mg/kg SC on day 8. The co-administration of these two doses resulted in a near elimination of circulating neutrophils (29 cells/ml). Leukocyte counts subsequently returned to normal levels by Day 18 (14 days post last dose). In conclusion, co-administration of SNS-595 and Ara-C reversibly ablates murine bone marrow cells and reversibly depletes circulating neutrophils. These data indicate that SNS-595 has the potential to combine effectively with Ara-C for the treatment of acute leukemias and suggests that additional studies in patients with advanced hematologic malignancies are warranted.
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