AR-67 is a novel, third-generation camptothecin analogue that has demonstrated high potency in preclinical studies and improved pharmacokinetic properties, as demonstrated by the increased stability of the active lactone form of AR-67 in blood samples. Preclinical studies and preliminary Phase I data confirm that AR-67 maintains a greater proportion of drug in the active lactone form as compared with approved second-generation products, a characteristic that Arno believes may translate to superior clinical activity. Moreover, the potential for oral administration may increase patient convenience.

Arno is currently conducting a single agent, ascending dose, Phase I clinical study of AR-67 in patients with advanced solid tumors. The study is evaluating the safety of AR-67, establishing the maximum tolerated dose, and characterizing the plasma PK profile. Multiple Phase II studies are planned for initiation in 2008 in a variety of cancers, including glioblastoma multiforme (GBM), a highly aggressive form of brain cancer.




Publications

• Bence AK, Mattingly CA, Burke TG and Adams VR, The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells. Cancer Chemother Pharmacol (2004) 54: 354-360.
• Bom D, Curran DP, Zhang J, Zimmer SG et al., The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity etc. Journal of Controlled Release 74 (2001) 325-333.
• Bom D, Curran DP, Kruszewski S, Zimmer SG et al., The Novel Silatecan 7-tert-Butyldimethylsilyl-10-hydroxycamptothecin Displays High Lipophilicity, Improved Human Blood Stability, and Potent Anticancer Activity. J. Med. Chem. 2000, 43, 3970-3980.
• Burke TG and Bom D, Camptothecin Design and Delivery Approaches for Elevating Anti-Topoisomerase I Activities in Vivo. Department of Pharmaceutical Sciences, College of Pharmacy, and the Experimental Therapeutics Program, Lucille P. Markey Cancer Center, University of Kentucky Medical Center.
• Chen AY, Shih SJ, Garriques LN et al., Silatecan DB-67 is a novel DNA topoisomerase I-targeted radiation sensitizer. Molecular Cancer Therapeutics 2005;4(2). February 2005.
• Du W, Kaskar B, Blumbergs P et al., Semisynthesis of DB-67 and Other Silatecans from Camptothecin by Thiol-Promoted Addition of Silyl Radicals. Bioorganic & Medicinal Chemistry 11 (2003) 451-458.
• Horn J, Jordan SL, Song K, Roberts MJ et al., Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma. Journal of Chromatography B 2006.
• Lopez Barcons LA, Zhang J, Siriwitayawan G et al., The Novel Highly Lipophilic Topoisomerase I Inhibitor DB-67 Is Effective in the Treatment of Liver Metastases of Murine CT-26 Colon Carcinoma. Neoplasia, Vol. 6, No. 5, September/October 2004, pp. 457-467.
• Pollack IF, Erff M, Bom D, Burke TG et al., Potent Topoisomerase I Inhibition by Novel Silatecans Eliminates Glioma Proliferation in Vitro and in Vivo. Cancer Research 59, 4898-4905, October 1, 1999.
• Song L, Bevins R and Anderson BD, Kinetics and Mechanisms of Activation of -Amino Acid Ester Prodrugs of Camptothecins. J. Med. Chem. 2006, 49, 4344-4355.
• Xiang TX and Anderson BD, Stable Supersaturated Aqueous Solutions of Silatecan 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin via Chemical Conversion in the Presence of a Chemically Modified ?-Cyclodextrin. Pharmaceutical Research, Vol. 19, No. 8, August 2002.