Genz-644282, a Novel Non-Camptothecin Topoisomerase I Inhibitor for Cancer Treatment

• Published in: Clinical cancer research Vol. 17; no. 9; pp. 2777 - 2787
• Main Authors: KURTZBERG, Leslie S, ROTH, Stephanie, FEI WANG, SCHMID, Steven M, LAVOIE, Edmond J, TEICHER, Beverly A, KRUMBHOLZ, Roy, CRAWFORD, Jennifer, BORMANN, Christy, DUNHAM, Sarah, MIN YAO, ROULEAU, Cecile, BAGLEY, Rebecca G, YU, Xian-Jie
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2011
• Subjects: Animal models; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Camptothecin - chemistry; Camptothecin - pharmacology; Cell Proliferation - drug effects; Cells, Cultured; HCT116 Cells; HeLa Cells; HT29 Cells; Humans; Male; Medical sciences; Mice; Mice, Inbred BALB C; Models, Biological; Naphthyridines - pharmacology; Naphthyridines - therapeutic use; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacology. Drug treatments; Topoisomerase I Inhibitors - pharmacology; Topoisomerase I Inhibitors - therapeutic use; Xenograft Model Antitumor Assays; Antineoplastic agent; Alkaloid; Isomerases; Treatment; Enzyme; DNA topoisomerase; Enzyme inhibitor; Malignant tumor; Topoisomerase I inhibitor; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-0542

Genz-644282 [8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one] has emerged as a promising candidate for antitumor agents. This report describes the bone marrow colony-forming unit, granulocyte macrophage (CFU-GM) and tumor cell CFU activity of topoisomerase I (Top1) inhibitors, such as Genz-644282, topotecan, irinotecan/SN-38, and ARC-111, and examines their activity in several human tumor xenograft models. Colony-forming assays were conducted with mouse and human bone marrow and eight human tumor cell lines. In addition, 29 human tumor cell lines representing a range of histology and potential resistance mechanisms were assayed for sensitivity to Genz-644282 in a 72-hour exposure assay. The efficacy of Genz-644282 was compared with standard anticancer drugs (i.e., irinotecan, docetaxel, and dacarbazine) in human tumor xenografts of colon cancer, renal cell carcinoma, non-small cell lung cancer, and melanoma. Human bone marrow CFU-GM was more sensitive to the Top1 inhibitors than was mouse bone marrow CFU-GM. The ratio of mouse to human IC(90) values was more than 10 for the camptothecins and less than 10 for Genz-644282, which had more potency as a cytotoxic agent toward human tumor cells in culture than the camptothecins in the colony-forming and 72-hour proliferation assays. Genz-644282 has superior or equal antitumor activity in the human tumor xenografts than the standard drug comparators. On the basis of preclinical activity and safety, Genz-644282 was selected for development and is currently undergoing phase 1 clinical trial.