title: Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  On the basis of preclinical activity and safety, Genz-644282 was selected for development and is currently undergoing phase 1 clinical trial.
authors.affiliation: Genzyme Corporation, Framingham, Massachussetts 01701, USA. Leslie.Kurtzberg@Genzyme.com
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kurtzberg
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roth
authors.forename: Roy
authors.initials: R
authors.lastname: Krumbholz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Crawford
authors.forename: Christy
authors.initials: C
authors.lastname: Bormann
authors.forename: Sarah
authors.initials: S
authors.lastname: Dunham
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.forename: Cecile
authors.initials: C
authors.lastname: Rouleau
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Bagley
authors.forename: Xian-Jie
authors.initials: XJ
authors.lastname: Yu
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Steven M
authors.initials: SM
authors.lastname: Schmid
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Lavoie
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C560916:Genz-644282; D009287:Naphthyridines; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin