Voreloxin, a first-in-class anticancer quinolone derivative, acts synergistically with cytarabine in vitro and induces bone marrow aplasia in vivo

Abstract

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.

Acute myeloid leukaemia in the elderly: a review

“…Arsenic trioxide combined with LDAC in elderly patients with AML resulted in a 30% CR rate and was relatively well tolerated (Roboz et al, 2008). Voreloxin, a novel topoisomerase II inhibitor, is completing early phase trials and may be synergistic in combination with cytarabine (Scatena et al, 2010). Finally, the plant-derived compound parthenolide, which inhibits NF-kB and specifically targets AML stem and progenitor cells (Guzman et al, 2007), is a promising compound.…”

Enhancement of radiosensitivity by the novel anticancer quinolone derivative vosaroxin in preclinical glioblastoma models

“…Maximum concentration in the cerebrum was 0.744 µgeq/g or 1.85 µMeq/g and in the cerebellum was 0.811 µgeq/g or 2.02 µMeq/g. Although brain tissues (cerebrum and cerebellum) showed tissue:plasma ratios ≤ 1.5, radioactivity in the brain achieved concentrations associated with anticancer activity in vitro [32,39]. These data suggested that active levels of vosaroxin may be achieved in the brain clinically where dose levels similar to or higher than 60 mg/m 2 have been investigated [37,49,50].…”

“…It has www.impactjournals.com/oncotarget been shown to be active against various preclinical models and demonstrated synergistic activity in combination with other antineoplastic agents [29][30][31][32][33][34][35].…”

“…Vosaroxin is not a substrate for P-glycoprotein drug pumps, and can induce apoptosis independent of p53, thereby avoiding two common mechanisms of drug resistance [29]. Vosaroxin has been shown to be active against various in vitro and in vivo tumor models including breast, bladder, pancreas, colon, ovarian, gastric, and lung cancer [29][30][31][32][33][34][35]. It has also shown synergistic activity with platinum agents, anthracyclines, antimetabolites, and targeted therapies in tumor models [36].…”

Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML?

“…Preclinical studies have demonstrated effective synergy when vosaroxin was combined with cytarabine (Ara-C) [48,51]. Authors suggested this enhanced cytotoxicity is likely the result of cells exiting S phase with cytarabine-induced DNA damage and entering G2 phase, unable to repair these DNA DSB and sustaining further insult as a result of the action of vosaroxin.…”