Voreloxin, formerly SNS-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models

Abstract

Voreloxin, formerly known as SNS-595 or AG-7352, is a novel naphthyridine analog currently under investigation for the treatment of ovarian and hematologic malignancies. Voreloxin mechanism of action includes DNA intercalation and inhibition of topoisomerase II that causes selective DNA damage. In this study, we describe the anti-proliferative activity of voreloxin in a wide range of in vitro and in vivo models of human cancers. The cytotoxicity of voreloxin in vitro was examined by MTT assay in 15 cell lines, including 4 drug-resistant lines. Activation of caspase in cell lines and tumors was evaluated by immunohistochemistry. Anti-tumor activity was assessed in 16 xenograft and 3 syngeneic tumor models in mice. Tumors were allowed to grow to approximately 150 mm(3) prior to treatment with voreloxin or comparator drugs. Activity of the anti-cancer agents was determined by calculating the inhibition rate (IR = [1 - (average tumor weight treated/average tumor weight control)] x 100%) and survival ratio (number surviving mice/number of mice per group at start of study) for each agent and dose and schedule tested. In vitro studies demonstrated voreloxin has broad anti-proliferative activity in 11 tumor cell lines, with IC(50) values ranging from 0.04 to 0.97 muM. Similar activity was observed in vitro in drug-resistant cell lines, including those that overexpress P-glycoprotein and have reduced topoisomerase levels. After a single intravenous dose, voreloxin concentrations in tumor were correlated with induction of the apoptosis marker caspase-3. The optimal dose and schedule was established using a KB nasopharyngeal carcinoma xenograft model. Administration of voreloxin at 20 mg/kg weekly for five doses effectively inhibited tumor growth (86%). Voreloxin demonstrated strong dose-dependent tumor growth inhibition (63-88%) in 10 of 11 solid tumor (breast, ovarian, colon, lung, gastric, and melanoma) xenograft models, 2 hematologic tumor xenograft models, 3 multidrug resistant tumor models and 3 murine syngeneic tumor models (Colon 26, Lewis Lung carcinoma, M5076 Ovarian Sarcoma). These data demonstrate that voreloxin is a broadly active anti-tumor agent in vitro and in vivo, with potent activity in aggressive and drug-resistant tumor models.