title: Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program.
abstract: BACKGROUND
  Genz-644282 is a novel non-camptothecin topoisomerase I poison that is in clinical development.
  
  
  METHODS
  Genz-644282 was tested against the PPTP in vitro panel (0.1 nM to 1 µM), and in vivo using three times per week × 2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4 mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1 mg/kg in 3 models to assess the dose-response relationship. mRNA gene signatures predictive for Genz-644282 response in vitro were applied to select 15 tumor models that were evaluated prospectively.
  
  
  RESULTS
  In vitro, Genz-644282 demonstrated potent cytotoxic activity with a median IC(50) of 1.2 nM (range 0.2-21.9 nM). In vivo, Genz-644282 at its MTD (4 mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2 mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1 mg/kg. Further testing at 2 mg/kg showed that Genz-644282 induced objective regressions in 7 of 17 (41%) models. There was a significant correlation between predictive response scores based on Affymetrix U133Plus2 baseline tumor expression profiles and the observed in vivo responses to Genz-644282.
  
  
  CONCLUSIONS
  Genz-644282 was highly active within a narrow dose range (2-4 mg/kg), typical of other topoisomerase I poisons. As with other topoisomerase I poisons, how accurately these data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent.
authors.affiliation: Nationwide Children's Hospital, Columbus, OH, USA. Peter.Houghton@nationwidechildrens.org
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: E
authors.initials: E
authors.lastname: Anders Kolb
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Mindy X
authors.initials: MX
authors.lastname: Zhang
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Madden
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D018572:Disease-Free Survival; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009287:Naphthyridines / Q000627:therapeutic use*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D015996:Survival Rate; D059004:Topoisomerase I Inhibitors / Q000627:therapeutic use*; D019772:Topotecan / Q000627:therapeutic use; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C560916:Genz-644282; D009287:Naphthyridines; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human