Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor

Abstract

The relative distribution of gefitinib-related material in nude mice bearing s.c. human tumor xenografts and in an orthotopic rat lung tumor model was investigated following oral administration (50 mg/kg) of [14 C]-gefitinib. Selected tissue samples were monitored for radioactivity by liquid scintillation counting, whereas plasma and tumor extracts were assayed for gefitinib and its major metabolites (M523595 and M537194) by high-performance liquid chromatography with tandem mass spectrometric detection. Tissue distribution was also determined by whole body autoradiography. Gefitinib was extensively distributed into the tissues of tumor-bearing mice and unchanged gefitinib was shown to account for most of the tumor radioactivity. Concentrations of gefitinib in mouse s.c. tumor xenografts were similar to skin concentrations and substantially greater (up to 12-fold based on area under the concentration-time curve) than plasma. Concentrations of gefitinib-related material in an orthotopic rat lung tumor were similar to those in healthy lung tissue and were much higher than corresponding blood levels. Following treatment of breast cancer patients with oral gefitinib (Iressa) 250 mg/d for z z z14 days, gefitinib concentrations (mean, 7.5 A Ag/g, 16.7 A Amol/L) in breast tumor tissue were 42 times higher than plasma, confirming the preferential distribution of gefitinib from blood into tumor tissue in the clinical situation. These gefitinib tumor concentrations are considerably higher than those reportedly required in vitro to achieve complete inhibition of epidermal growth factor receptor autophosphorylation in both epidermal growth factor receptor mutant (0.2 A Amol/L) and wild-type cells (2 A Amol/L). [Mol Cancer Ther 2005;4(4):641 -9]

Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib—A Phase II Trial

“…Patients were moved onto non-EIAEDs before study entry, to exclude reduced drug exposure through induction of CYP3A4. Intratumoral gefitinib concentrations reached 22-fold higher concentrations in the resected tumor tissue than in coincident plasma samples, consistent with previous reports from lung and breast cancer (28,29 Figure 5. Modulation of the EGFR signaling pathway.…”

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…Despite the technical problems associated with phosphoprotein immunostaining and the fact that these two studies were not designed to specifically determine target inactivation in HER2-overexpressing tumors at maximal drug dosage, they do appear to suggest that the drugs do reach their tumor targets and at least partially inactivate them. Tumor biodistribution does not seem to be a limiting step since, at least with regards to gefitinib, tumor and tissue concentrations have been measured and are much higher than serum concentrations and well above concentrations that fully suppress EGFR and HER2 signaling in cell-culture models (McKillop et al, 2005). (Sergina et al, 2007).…”

The HER family and cancer: emerging molecular mechanisms and therapeutic targets

“…These studies appear to show that TKIs do reduce EGFR and HER2 autophosphorylation and downstream MAPK signaling, however a reduction in Akt signaling has not been seen 80,81 . Tissue biodistribution does not seem to be a limitation and at least in the case of gefitinib, drug levels in tumor tissue appear to be well within the expected therapeutic range 82 . Our laboratory recently gained considerable insight into breast cancer resistance when we found that HER3 escapes inhibition by TKI therapy in HER2-overexpressing breast cancers 83 .…”