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


OBJECTIVE
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.
Scatena
Caroline D
CD
Sunesis Pharmaceuticals, Inc., South San Francisco, CA, 94080, USA.
Kumer
Jeffrey L
JL
Arbitrario
Jennifer P
JP
Howlett
Anthony R
AR
Hawtin
Rachael E
RE
Fox
Judith A
JA
Silverman
Jeffrey A
JA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009287:Naphthyridines; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D013844:Thiazoles
D009287:Naphthyridines; D013844:Thiazoles; D003561:Cytarabine; C485113:vosaroxin