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

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-β kinase antagonist, was administered orally. Plasma levels of LY2157299, percentage of phosphorylated Smad2,3 (pSmad) in tumour, a...

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Bibliographic Details
Published in:European journal of cancer (1990) 2008-01, Vol.44 (1), p.142-150
Main Authors: Bueno, Lorea, de Alwis, Dinesh P, Pitou, Celine, Yingling, Jonathan, Lahn, Michael, Glatt, Sophie, Trocóniz, Iñaki F
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
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
Hematology, Oncology and Palliative Medicine
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Medical sciences
Mice
Mice, Nude
Neoplasm Transplantation
Pharmacology. Drug treatments
PK/PD
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Receptors, Transforming Growth Factor beta - antagonists & inhibitors
Semi-mechanistic modelling
Signal pathway modulation
TGF-β inhibition
Transplantation, Heterologous
Tumors
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Summary: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-β 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 [ t1/2 (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-β membrane receptor type I.
ISSN:0959-8049
1879-0852
DOI:10.1016/j.ejca.2007.10.008