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

L Bueno, DP de Alwis, C Pitou, J Yingling… - European journal of …, 2008 - Elsevier
L Bueno, DP de Alwis, C Pitou, J Yingling, M Lahn, S Glatt, IF Trocóniz
European journal of cancer, 2008Elsevier
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 …
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.
Elsevier