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

Scatena CD, Kumer JL, Arbitrario JP, Howlett AR, Hawtin RE, Fox JA, Silverman JA - Cancer Chemother. Pharmacol. (2010)

Bottom Line: Combination index (CI) analysis established the effect of the drugs in combination.The two drugs had additive or synergistic activity in vitro and supra-additive activity in vivo.These data support ongoing clinical evaluation of voreloxin both alone and in combination with cytarabine for the treatment of AML.

View Article: PubMed Central - PubMed

Affiliation: Sunesis Pharmaceuticals, Inc., South San Francisco, CA, 94080, USA.

ABSTRACT

Main purpose: Voreloxin 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 questions: Is single agent voreloxin active in preclinical models of AML? Does the combination of voreloxin and cytarabine enhance the activity of either agent alone?

Methods: Inhibition 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.

Results: Voreloxin 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.

Conclusions: These data support ongoing clinical evaluation of voreloxin both alone and in combination with cytarabine for the treatment of AML.

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Related in: MedlinePlus

Voreloxin and cytarabine in combination causes reversible neutropenia with a more modest impact on platelets CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. a Percent cellularity remaining in the bone marrow on days 6 (D6) and 12 (D12): Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 20 mg/kg SC tid q4d ×2; Voreloxin, 10 mg/kg IV q4d ×2; Combo, cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. b Peripheral blood was isolated on days 6, 8, and 12 for analysis. Absolute neutrophils, absolute lymphocytes, and platelets (×103/μl) in circulation following treatment: (Filled square), vehicle; (Triangle), cytarabine, 20 mg/kg SC tid q4d ×2; (Circle), voreloxin, 10 mg/kg IV q4d ×2; (Filled inverted triangle), combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. Black arrow represents the three cytarbine doses, and the gray arrow represents the voreloxin dose
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Fig4: Voreloxin and cytarabine in combination causes reversible neutropenia with a more modest impact on platelets CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. a Percent cellularity remaining in the bone marrow on days 6 (D6) and 12 (D12): Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 20 mg/kg SC tid q4d ×2; Voreloxin, 10 mg/kg IV q4d ×2; Combo, cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. b Peripheral blood was isolated on days 6, 8, and 12 for analysis. Absolute neutrophils, absolute lymphocytes, and platelets (×103/μl) in circulation following treatment: (Filled square), vehicle; (Triangle), cytarabine, 20 mg/kg SC tid q4d ×2; (Circle), voreloxin, 10 mg/kg IV q4d ×2; (Filled inverted triangle), combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. Black arrow represents the three cytarbine doses, and the gray arrow represents the voreloxin dose

Mentions: To determine whether the treatment-induced bone marrow ablation was reversible, repeat studies were extended to day 12 with the inclusion of peripheral blood counts along with bone marrow cellularity. CD-1 mice were treated with voreloxin, cytarabine, or the two drugs combined. In animals treated with voreloxin at 20 mg/kg on days zero and four (MTD), relative to vehicle-treated animals, bone marrow cellularity was reduced by 78% on day 6, while in animals treated with cytarabine at 60 mg/kg tid on days zero and four (MTD) marrow cellularity decreased 42% (Fig. 3a). These decreases in cellularity were reversible for both agents with bone marrow returning to 100% cellularity by day 12 (Fig. 3a). The bone marrow in vehicle-treated animals was unaffected by treatment (Fig. 3a). Consistent with results of the experiment previously described in Fig. 2, when animals received the combination of voreloxin (10 mg/kg q4d ×2) with cytarabine (20 mg/kg tid q4d ×2) bone marrow cellularity was reduced by 91% relative to vehicle on day 6 (Fig. 4a, D6). The marrow recovered from combination treatment with mean cellularity returning to 90% or greater 8 days after completing treatment (Fig. 4a, D12).Fig. 3


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

Scatena CD, Kumer JL, Arbitrario JP, Howlett AR, Hawtin RE, Fox JA, Silverman JA - Cancer Chemother. Pharmacol. (2010)

Voreloxin and cytarabine in combination causes reversible neutropenia with a more modest impact on platelets CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. a Percent cellularity remaining in the bone marrow on days 6 (D6) and 12 (D12): Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 20 mg/kg SC tid q4d ×2; Voreloxin, 10 mg/kg IV q4d ×2; Combo, cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. b Peripheral blood was isolated on days 6, 8, and 12 for analysis. Absolute neutrophils, absolute lymphocytes, and platelets (×103/μl) in circulation following treatment: (Filled square), vehicle; (Triangle), cytarabine, 20 mg/kg SC tid q4d ×2; (Circle), voreloxin, 10 mg/kg IV q4d ×2; (Filled inverted triangle), combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. Black arrow represents the three cytarbine doses, and the gray arrow represents the voreloxin dose
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Related In: Results  -  Collection

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Fig4: Voreloxin and cytarabine in combination causes reversible neutropenia with a more modest impact on platelets CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. a Percent cellularity remaining in the bone marrow on days 6 (D6) and 12 (D12): Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 20 mg/kg SC tid q4d ×2; Voreloxin, 10 mg/kg IV q4d ×2; Combo, cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. b Peripheral blood was isolated on days 6, 8, and 12 for analysis. Absolute neutrophils, absolute lymphocytes, and platelets (×103/μl) in circulation following treatment: (Filled square), vehicle; (Triangle), cytarabine, 20 mg/kg SC tid q4d ×2; (Circle), voreloxin, 10 mg/kg IV q4d ×2; (Filled inverted triangle), combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2. Black arrow represents the three cytarbine doses, and the gray arrow represents the voreloxin dose
Mentions: To determine whether the treatment-induced bone marrow ablation was reversible, repeat studies were extended to day 12 with the inclusion of peripheral blood counts along with bone marrow cellularity. CD-1 mice were treated with voreloxin, cytarabine, or the two drugs combined. In animals treated with voreloxin at 20 mg/kg on days zero and four (MTD), relative to vehicle-treated animals, bone marrow cellularity was reduced by 78% on day 6, while in animals treated with cytarabine at 60 mg/kg tid on days zero and four (MTD) marrow cellularity decreased 42% (Fig. 3a). These decreases in cellularity were reversible for both agents with bone marrow returning to 100% cellularity by day 12 (Fig. 3a). The bone marrow in vehicle-treated animals was unaffected by treatment (Fig. 3a). Consistent with results of the experiment previously described in Fig. 2, when animals received the combination of voreloxin (10 mg/kg q4d ×2) with cytarabine (20 mg/kg tid q4d ×2) bone marrow cellularity was reduced by 91% relative to vehicle on day 6 (Fig. 4a, D6). The marrow recovered from combination treatment with mean cellularity returning to 90% or greater 8 days after completing treatment (Fig. 4a, D12).Fig. 3

Bottom Line: Combination index (CI) analysis established the effect of the drugs in combination.The two drugs had additive or synergistic activity in vitro and supra-additive activity in vivo.These data support ongoing clinical evaluation of voreloxin both alone and in combination with cytarabine for the treatment of AML.

View Article: PubMed Central - PubMed

Affiliation: Sunesis Pharmaceuticals, Inc., South San Francisco, CA, 94080, USA.

ABSTRACT

Main purpose: Voreloxin 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 questions: Is single agent voreloxin active in preclinical models of AML? Does the combination of voreloxin and cytarabine enhance the activity of either agent alone?

Methods: Inhibition 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.

Results: Voreloxin 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.

Conclusions: These data support ongoing clinical evaluation of voreloxin both alone and in combination with cytarabine for the treatment of AML.

Show MeSH
Related in: MedlinePlus