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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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Voreloxin and cytarabine, alone or in combination, ablate normal bone marrow CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. On day 6, femurs were isolated, and cellularity was assessed in H&E stained bone marrow sections. a Percent cellularity remaining in the bone marrow following treatment: Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 60 mg/kg SC tid q4d ×2; Voreloxin, 20 mg/kg IV q4d ×2. b Percent cellularity remaining in the bone marrow following treatment: Vehicle, as in (a); 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. c H&E stained femur sections, original magnification ×100: i. vehicle, as in (a); ii. cytarabine, 60 mg/kg SC tid q4d ×2; iii. voreloxin, 20 mg/kg IV q4d ×2; iv. cytarabine, 20 mg/kg SC tid q4d ×2; v. voreloxin, 10 mg/kg IV q4d ×2; vi. combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2
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Fig2: Voreloxin and cytarabine, alone or in combination, ablate normal bone marrow CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. On day 6, femurs were isolated, and cellularity was assessed in H&E stained bone marrow sections. a Percent cellularity remaining in the bone marrow following treatment: Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 60 mg/kg SC tid q4d ×2; Voreloxin, 20 mg/kg IV q4d ×2. b Percent cellularity remaining in the bone marrow following treatment: Vehicle, as in (a); 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. c H&E stained femur sections, original magnification ×100: i. vehicle, as in (a); ii. cytarabine, 60 mg/kg SC tid q4d ×2; iii. voreloxin, 20 mg/kg IV q4d ×2; iv. cytarabine, 20 mg/kg SC tid q4d ×2; v. voreloxin, 10 mg/kg IV q4d ×2; vi. combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2

Mentions: The activity of voreloxin was investigated in vivo by examining the effect of the drug in a mouse model of bone marrow ablation and recovery. CD-1 mice were administered vehicle, voreloxin, cytarabine, or a combination of voreloxin and cytarabine. Two days after completion of the treatment cycle (day 6), femurs were isolated, and bone marrow cellularity was assessed in hematoxylin-eosin (H&E) stained sections. The mean bone marrow cellularity was 95% in the vehicle-treated animals indicating that the hematopoietic cells in the bone marrow were unaffected by the procedures, and the marrow was normal (Fig. 2a; c i). Administration of cytarabine at the maximum tolerated dose (MTD), 60 mg/kg tid q4d ×2, caused a 26% reduction in bone marrow cellularity relative to vehicle by day six (Fig. 2a). In comparison, administration of voreloxin at MTD, 20 mg/kg q4d ×2, resulted in an 80% reduction in cellularity relative to vehicle 2 days after treatment (Fig. 2a). In cytarabine-treated or voreloxin-treated animals, the percentage of hematopoietic cells in the marrow decreased in association with increased signs of marrow damage [10, 19] including dilation of sinusoids with infiltration of adipocytes and erythrocytes into the marrow stroma (Fig. 2c ii, iii).Fig. 2


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, alone or in combination, ablate normal bone marrow CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. On day 6, femurs were isolated, and cellularity was assessed in H&E stained bone marrow sections. a Percent cellularity remaining in the bone marrow following treatment: Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 60 mg/kg SC tid q4d ×2; Voreloxin, 20 mg/kg IV q4d ×2. b Percent cellularity remaining in the bone marrow following treatment: Vehicle, as in (a); 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. c H&E stained femur sections, original magnification ×100: i. vehicle, as in (a); ii. cytarabine, 60 mg/kg SC tid q4d ×2; iii. voreloxin, 20 mg/kg IV q4d ×2; iv. cytarabine, 20 mg/kg SC tid q4d ×2; v. voreloxin, 10 mg/kg IV q4d ×2; vi. combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2
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Fig2: Voreloxin and cytarabine, alone or in combination, ablate normal bone marrow CD-1 mice received vehicle, voreloxin, cytarabine, or voreloxin and cytarabine in combination on day 0 and 4. On day 6, femurs were isolated, and cellularity was assessed in H&E stained bone marrow sections. a Percent cellularity remaining in the bone marrow following treatment: Vehicle, 0.17% methanesulfonic acid in 5% sorbitol IV q4d ×2 and water SC tid q4d ×2; Cytarabine, 60 mg/kg SC tid q4d ×2; Voreloxin, 20 mg/kg IV q4d ×2. b Percent cellularity remaining in the bone marrow following treatment: Vehicle, as in (a); 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. c H&E stained femur sections, original magnification ×100: i. vehicle, as in (a); ii. cytarabine, 60 mg/kg SC tid q4d ×2; iii. voreloxin, 20 mg/kg IV q4d ×2; iv. cytarabine, 20 mg/kg SC tid q4d ×2; v. voreloxin, 10 mg/kg IV q4d ×2; vi. combo: cytarabine, 20 mg/kg SC tid q4d ×2, and voreloxin, 10 mg/kg IV q4d ×2
Mentions: The activity of voreloxin was investigated in vivo by examining the effect of the drug in a mouse model of bone marrow ablation and recovery. CD-1 mice were administered vehicle, voreloxin, cytarabine, or a combination of voreloxin and cytarabine. Two days after completion of the treatment cycle (day 6), femurs were isolated, and bone marrow cellularity was assessed in hematoxylin-eosin (H&E) stained sections. The mean bone marrow cellularity was 95% in the vehicle-treated animals indicating that the hematopoietic cells in the bone marrow were unaffected by the procedures, and the marrow was normal (Fig. 2a; c i). Administration of cytarabine at the maximum tolerated dose (MTD), 60 mg/kg tid q4d ×2, caused a 26% reduction in bone marrow cellularity relative to vehicle by day six (Fig. 2a). In comparison, administration of voreloxin at MTD, 20 mg/kg q4d ×2, resulted in an 80% reduction in cellularity relative to vehicle 2 days after treatment (Fig. 2a). In cytarabine-treated or voreloxin-treated animals, the percentage of hematopoietic cells in the marrow decreased in association with increased signs of marrow damage [10, 19] including dilation of sinusoids with infiltration of adipocytes and erythrocytes into the marrow stroma (Fig. 2c ii, iii).Fig. 2

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