title: Preclinical evaluation of the novel multi-targeted agent R1530.
abstract: OBJECTIVE
  This study describes the antiproliferative activity of the multikinase inhibitor R1530 in vitro and its antitumor and anti-angiogenic activity, pharmacokinetics, and tolerability in vivo.
  
  
  METHODS
  The antiproliferative activity of R1530 was investigated in a range of human tumor, endothelial and fibroblast cell lines. Tolerability and antitumor activity were assessed in mice bearing a range of human tumor xenografts, and anti-angiogenic properties were established in the murine corneal pocket assay. R1530 pharmacokinetics in mice were established.
  
  
  RESULTS
  R1530 strongly inhibited human tumor cell proliferation. Growth factor-driven proliferation of endothelial and fibroblast cells was also inhibited. Significant tumor growth inhibition was demonstrated in a lung cancer xenograft model with a range of once daily, weekly and twice-weekly doses of R1530 (3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw). Daily doses were most effective in the lung cancer model and also had significant growth inhibitory effects in models of colorectal, prostate, and breast tumors. Tumor regression occurred in all models treated with the maximum tolerated daily dose (50 mg/kg). The doses of 25 and 50 mg/kg qd resulted in biologically significant increased survival in all tested models. After oral administration in nude mice, R1530 showed good tissue penetration. Exposure was dose dependent up to 100 mg/kg with oral administration.
  
  
  CONCLUSIONS
  R1530 has demonstrated activity against a range of tumor models in vitro and in vivo and is an effective inhibitor of angiogenesis. These findings support the approach of targeting multiple pathways in the search for potential agents with improved anticancer properties.
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc, Nutley, NJ 07110, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Christian
authors.initials: C
authors.lastname: Tovar
authors.forename: Yu-E
authors.initials: YE
authors.lastname: Zhang
authors.forename: Aruna
authors.initials: A
authors.lastname: Railkar
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Daisy
authors.initials: D
authors.lastname: Carvajal
authors.forename: Thomas
authors.initials: T
authors.lastname: Nevins
authors.forename: Wanping
authors.initials: W
authors.lastname: Geng
authors.forename: Michael
authors.initials: M
authors.lastname: Linn
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.forename: Zhuming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Wovkulich
authors.forename: Grace
authors.initials: G
authors.lastname: Ju
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: C555028:5-(2-chlorophenyl)-7-fluoro-1,2-dihydro-8-methoxy-3-methylpyrazol(3,4b)(1,4)benzodiazepine; D000970:Antineoplastic Agents; D011720:Pyrazoles; D042461:Vascular Endothelial Growth Factor A; D001569:Benzodiazepines