Voreloxin a firstinclass anticancer quinolone d

Authors: Caroline D Scatena Jeffrey L Kumer Jennifer P Arbitrario Anthony R Howlett Rachael E Hawtin Judith A Fox Jeffrey A Silverman

Publish Date: 2010/01/08

Volume: 66, Issue: 5, Pages: 881-888

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Abstract

Voreloxin is a firstinclass anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II inducing siteselective 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 programInhibition of proliferation was studied in three cancer cell lines HL60 acute promyelocytic leukemia MV411 AML and CCRFCEM 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 recoveryVoreloxin 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 supraadditive 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 paradigmThe standard treatment for newly diagnosed acute myeloid leukemia AML has not changed appreciably in the last few decades Anthracyclines along with the anthracenedione mitoxantrone in combination with cytarabine a nucleoside analog remain the mainstays of treatment 28 29 Despite the efficacy of anthracyclinebased therapies patients with AML typically relapse and many fail to respond to their initial induction therapy 28 29 Therapy for relapsed AML is rarely curative unless the patient undergoes an allogeneic bone marrow transplant BMT and most patients die from their disease 23 28 29 Given that AML is primarily a disease of older patients with a median age of diagnosis of 67 years only a minority of patients will be eligible for BMT 30 Clearly a need exists for alternative therapies for the treatment of this disease including opportunities for bridging to the potentially curative option of hematopoietic stem cell transplantVoreloxin is a firstinclass anticancer quinolone derivative that is currently in clinical studies as a single agent for the newly diagnosed elderly population and in combination with cytarabine for relapsed/refractory AML Voreloxin’s mechanism of action is similar to that of the anthracyclines 4 in that it is a DNA damaging agent that intercalates DNA and poisons topoisomerase II 12 However because voreloxin is derived from a distinct chemical scaffold both mechanistic and pharmaceutical features differentiate this new agent The naphthyridine core a member of the quinolone family is less chemically reactive than that of the anthracyclines The voreloxininduced DNA damage in contrast to anthracyclines is siteselective targeting GC rich regions similar to quinolone antibacterial drugs 12 Voreloxin also has a favorable pharmacokinetic profile with low clearance 2 L/h/m2 long terminal halflife 22 h and doseproportional exposure 1 Voreloxin’s 50 L/m2 volume of distribution at steady state exceeds total body water but is at least eightfold lower than that of the anthracycline daunomycin 2 27 Taken together the siteselective DNA damage and more limited distribution to normal tissues suggest a lower potential for the offtarget organ toxicities common to the anthracyclines 15 Thus far in clinical studies the doselimiting toxicities observed with voreloxin are reversible and include oral mucositis leukemias 18 25 and neutropenia with an acceptable frequency of febrile neutropenia solid tumors 1

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