Antitumor activity of XR5944, a novel and potent topoisomerase poison

Inhibitors of topoisomerases are widely used in the treatment of cancer, in cluding inhibitors of topoisomerase I (camptothecin analogs such as irinote can and topotecan) and topoisomerase II (etoposide and doxorubicin). The no vel bis-phenazine, XR5944, is a joint inhibitor of topoisomerase I and II a s shown by the stabilization of topoisomerase-dependent cleavable complexes . XR5944 demonstrated exceptional activity against human and murine tumor c ells in vitro and in vivo. In a range of cell lines XR5944 (IC50 0.04-0.4 n M) was significantly more potent than TAS-103, originally proposed as a joi nt topoisomerase I and II inhibitor, as well as agents specific for topoiso merase I or II (topotecan, doxorubicin and etoposide). In addition, XR5944 was unaffected by atypical drug resistance and retained significant activit y in cells overexpressing P-glycoprotein or multidrug resistance-associated protein. Antitumor efficacy of XR5944 was demonstrated in human carcinoma xenograft models (H69 small cell lung cancer and HT29 colon). In the HT29 m odel, which is relatively unresponsive to chemotherapy, XR5944 (15 mg/kg i. v., q4d x 3) induced tumor regression in the majority of animals (six of ei ght), whereas TAS-103, dosed at its maximum tolerated dose (45 mg/kg i.v., q7d x 3), only induced a delay in tumor growth compared with control animal s. In the H69 model, low doses of XR5944 (5 mg/kg i.v., qd x 5/week for 2 w eeks or 10-15 mg/kg i.v., q4d x 3), induced complete tumor regression in th e majority of animals. In contrast, topotecan (20 mg/kg i.v., q4d x 3) or e toposide (30 mg/kg i.v., q5d x 5) only slowed the tumor growth rate. These studies show that XR5944 is a highly active novel anticancer agent that is well tolerated at efficacious doses. [(C) 2001 Lippincott Williams & Wilkin s.].