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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 combined with cytarabine has additive or synergistic activity in acute leukemia cell lines Viability studies were performed using human acute leukemia cell lines MV4-11, HL-60, and CCRF-CEM exposed for 72 h to serially diluted voreloxin and/or cytarabine. a Percent viability of cells treated with voreloxin alone or in combination: (Filled circle), voreloxin alone; (Filled inverted triangle), voreloxin combined with cytarabine. The combination index (CI) calculated from the curves is indicated and also shown graphically below. b Combination index (CI): CI < 0.85 indicates synergy, CI of 0.85–1.2 indicates additivity, CI > 1.2 indicates antagonism. Each data point represents an independent experiment. (triangle), CCRF-CEM; (Circle), MV4-11; (Square), HL-60. Voreloxin control, voreloxin combined with itself
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Fig1: Voreloxin combined with cytarabine has additive or synergistic activity in acute leukemia cell lines Viability studies were performed using human acute leukemia cell lines MV4-11, HL-60, and CCRF-CEM exposed for 72 h to serially diluted voreloxin and/or cytarabine. a Percent viability of cells treated with voreloxin alone or in combination: (Filled circle), voreloxin alone; (Filled inverted triangle), voreloxin combined with cytarabine. The combination index (CI) calculated from the curves is indicated and also shown graphically below. b Combination index (CI): CI < 0.85 indicates synergy, CI of 0.85–1.2 indicates additivity, CI > 1.2 indicates antagonism. Each data point represents an independent experiment. (triangle), CCRF-CEM; (Circle), MV4-11; (Square), HL-60. Voreloxin control, voreloxin combined with itself

Mentions: The activity of voreloxin in combination with cytarabine was then assessed using drug concentrations extrapolated from individual IC50 values. When voreloxin and cytarabine were combined, the cytotoxic activity in MV4-11 and HL-60 cells was synergistic as demonstrated by a leftward shift in the voreloxin IC50 curves and calculated CIs less than 0.85 (Fig. 1a, b). In CCRF-CEM cells, combining voreloxin with cytarabine resulted in an additive increase in cytotoxicity with CIs of 0.85 (Fig. 1b) and 0.99 (Fig. 1a, b).Fig. 1


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 combined with cytarabine has additive or synergistic activity in acute leukemia cell lines Viability studies were performed using human acute leukemia cell lines MV4-11, HL-60, and CCRF-CEM exposed for 72 h to serially diluted voreloxin and/or cytarabine. a Percent viability of cells treated with voreloxin alone or in combination: (Filled circle), voreloxin alone; (Filled inverted triangle), voreloxin combined with cytarabine. The combination index (CI) calculated from the curves is indicated and also shown graphically below. b Combination index (CI): CI < 0.85 indicates synergy, CI of 0.85–1.2 indicates additivity, CI > 1.2 indicates antagonism. Each data point represents an independent experiment. (triangle), CCRF-CEM; (Circle), MV4-11; (Square), HL-60. Voreloxin control, voreloxin combined with itself
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2921053&req=5

Fig1: Voreloxin combined with cytarabine has additive or synergistic activity in acute leukemia cell lines Viability studies were performed using human acute leukemia cell lines MV4-11, HL-60, and CCRF-CEM exposed for 72 h to serially diluted voreloxin and/or cytarabine. a Percent viability of cells treated with voreloxin alone or in combination: (Filled circle), voreloxin alone; (Filled inverted triangle), voreloxin combined with cytarabine. The combination index (CI) calculated from the curves is indicated and also shown graphically below. b Combination index (CI): CI < 0.85 indicates synergy, CI of 0.85–1.2 indicates additivity, CI > 1.2 indicates antagonism. Each data point represents an independent experiment. (triangle), CCRF-CEM; (Circle), MV4-11; (Square), HL-60. Voreloxin control, voreloxin combined with itself
Mentions: The activity of voreloxin in combination with cytarabine was then assessed using drug concentrations extrapolated from individual IC50 values. When voreloxin and cytarabine were combined, the cytotoxic activity in MV4-11 and HL-60 cells was synergistic as demonstrated by a leftward shift in the voreloxin IC50 curves and calculated CIs less than 0.85 (Fig. 1a, b). In CCRF-CEM cells, combining voreloxin with cytarabine resulted in an additive increase in cytotoxicity with CIs of 0.85 (Fig. 1b) and 0.99 (Fig. 1a, b).Fig. 1

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