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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

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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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Acknowledgments

The authors would like to thank Dr. Carl L. Millward and Dr. Lisa H. Tai for pathology review, Aaron McCarty and his staff for animal husbandry support.

Conflict of interest statement

All authors are current or former employees of Sunesis Pharmaceuticals. The research was funded by Sunesis Pharmaceuticals.

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Authors and Affiliations

  1. Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA, 94080, USA

    Caroline D. Scatena, Jeffrey L. Kumer, Jennifer P. Arbitrario, Anthony R. Howlett, Rachael E. Hawtin, Judith A. Fox & Jeffrey A. Silverman

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  1. Caroline D. Scatena
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  2. Jeffrey L. Kumer
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  3. Jennifer P. Arbitrario
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  4. Anthony R. Howlett
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  7. Jeffrey A. Silverman
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Correspondence to Judith A. Fox.

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Scatena, C.D., Kumer, J.L., Arbitrario, J.P. et al. Voreloxin, a first-in-class anticancer quinolone derivative, acts synergistically with cytarabine in vitro and induces bone marrow aplasia in vivo. Cancer Chemother Pharmacol 66, 881–888 (2010). https://doi.org/10.1007/s00280-009-1234-z

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  • DOI: https://doi.org/10.1007/s00280-009-1234-z

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