%0 Journal Article
%T A mathematical model separates quantitatively the cytostatic and cytotoxic effects of a HER2 tyrosine kinase inhibitor
%A Peter Hinow
%A Shizhen Wang
%A Carlos L Arteaga
%A Glenn F Webb
%J Theoretical Biology and Medical Modelling
%D 2007
%I BioMed Central
%R 10.1186/1742-4682-4-14
%X The model suggests that lapatinib acts as expected by slowing the transition through G1 phase. However, the experimental data indicated a previously unreported late cytotoxic effect, which was incorporated into the model. Both effects depend on the dosage of the drug, which shows saturation kinetics.The model separates quantitatively the cytostatic and cytotoxic effects of lapatinib and may have implications for preclinical studies with other anti-oncogene therapies.Molecule-targeted anti-cancer drugs have been developed as a result of our understanding of tumor cell and molecular biology. Compared to "traditional" cancer therapies, targeted drugs such as the tyrosine kinase inhibitors (TKIs) have higher specificity and relatively lower toxicity in selected patients with corresponding oncogene expression. Members of the type 1 receptor tyrosine kinase (RTK) family, which includes the epidermal growth factor receptor (EGFR), HER2 (ErbB2), HER3 and HER4 play a crucial role in growth and differentiation of both normal and malignant mammary epithelial cells [1,2]. Binding of receptor-specific ligands to the ectodomain of EGFR, HER3 and HER4 results in the formation of receptor dimers and hetero-oligomers to which HER2 is recruited as the preferred heterodimerization partner [3]. HER2 gene amplification has been reported in approximately 20% of breast cancers, where it is associated with poor patient outcome [4]. Studies with HER2-overexpressing breast cancer cell lines and human tumors have shown constitutive phosphorylation of HER2 [5,6]. Overexpression of HER2 is associated with transformation of mammary epithelial cells [7,8] as well as shorter survival in patients with breast carcinoma [4,9]. These facts make HER2 a rational therapeutic target in human breast cancer. One therapeutic approach against HER2-overexpressing breast cancers is the generation of trastuzumab, a humanized IgG1 that binds to residues 529¨C626 in domain IV of the HER2 ectodomain [2,10]. However,
%U http://www.tbiomed.com/content/4/1/14