The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model

Oncogene. 2002 Mar 27;21(13):2089-96. doi: 10.1038/sj.onc.1205267.

Abstract

The therapeutic efficacy of synthetic inhibitors of matrix-metalloproteinases (MMPs) in various cancers has been demonstrated. A novel inhibitor, Ro 28-2653, with high selectivity for MMP2, MMP9 and membrane type 1-MMP was evaluated in an orthotopic prostate cancer rat model. Efficacy was determined by recording tumor growth and survival endpoints. Prostate cancer was induced by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral lobe of the prostates of 148 Copenhagen rats. Daily oral treatment with Ro 28-2653 (10-300 mg/kg per day) was started on day 1 or on day 6 after tumor cell injection. Animals were sacrificed on day 20 for determination of tumor weights. For survival studies, rats received daily oral Ro 28-2653 (100 mg/kg per day) or vehicle for up to 30 days. Tumor induction was successful in 100% of the animals. Ro 28-2653 reproducibly reduced the tumor weights by up to 90% in a dose-dependent manner. In addition, an inhibitory effect in rats with established tumors (treatment start at day 6) was shown. A significantly prolonged survival of Ro 28-2653-treated rats was also demonstrated. Selective inhibition of MMP activity is a novel therapeutic approach, which bears promise for studies in patients with prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use*
  • Male
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / metabolism
  • Neoplasm Transplantation
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology*
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use*
  • Rats
  • Survival Rate
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Piperazines
  • Pyrimidines
  • Ro 28-2653
  • Matrix Metalloproteinases