Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice

Eur J Cancer. 2008 Jan;44(1):142-50. doi: 10.1016/j.ejca.2007.10.008. Epub 2007 Nov 26.

Abstract

Human xenografts Calu6 (non-small cell lung cancer) and MX1 (breast cancer) were implanted subcutaneously in nude mice and LY2157299, a new type I receptor TGF-beta kinase antagonist, was administered orally. Plasma levels of LY2157299, percentage of phosphorylated Smad2,3 (pSmad) in tumour, and tumour size were used to establish a semi-mechanistic pharmacokinetic/pharmacodynamic model. An indirect response model was used to relate plasma concentrations with pSmad. The model predicts complete inhibition of pSmad and rapid turnover rates [t(1/2) (min)=18.6 (Calu6) and 32.0 (MX1)]. Tumour growth inhibition was linked to pSmad using two signal transduction compartments characterised by a mean signal propagation time with estimated values of 6.17 and 28.7 days for Calu6 and MX1, respectively. The model provides a tool to generate experimental hypothesis to gain insights into the mechanisms of signal transduction associated to the TGF-beta membrane receptor type I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Transplantation, Heterologous

Substances

  • Receptors, Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I