Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor
| Autor: | Nikolaus Hagedorn, John C. Panetta, Clinton F. Stewart, Christopher M. Waters, Charles H. Fraga, Yanli Zhuang, K. Elaine Hubbard |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Central Nervous System
Cancer Research Microdialysis Time Factors endocrine system diseases Abcg2 medicine.drug_class Administration Oral Antineoplastic Agents Biology Pharmacology Tyrosine-kinase inhibitor Mice Cerebrospinal fluid Gefitinib Extracellular fluid medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals ATP Binding Cassette Transporter Subfamily B Member 1 Protein Kinase Inhibitors Dose-Response Relationship Drug Brain Extracellular Fluid Blood Proteins Immunohistochemistry Mice Inbred C57BL Oncology Blood-Brain Barrier Area Under Curve Injections Intravenous biology.protein Quinazolines Choroid plexus Topotecan ATP-Binding Cassette Transporters Female Algorithms medicine.drug Protein Binding |
| Zdroj: | Cancer research. 66(23) |
| ISSN: | 0008-5472 |
| Popis: | A potential strategy to increase the efficacy of topotecan to treat central nervous system (CNS) malignancies is modulation of the activity of ATP-binding cassette (ABC) transporters at the blood-brain and blood-cerebrospinal fluid barriers to enhance topotecan CNS penetration. This study focused on topotecan penetration into the brain extracellular fluid (ECF) and ventricular cerebrospinal fluid (CSF) in a mouse model and the effect of modulation of ABC transporters at the blood-brain and blood-cerebrospinal fluid barriers by a tyrosine kinase inhibitor (gefitinib). After 4 and 8 mg/kg topotecan i.v., the brain ECF to plasma AUC ratio of unbound topotecan lactone was 0.21 ± 0.04 and 0.61 ± 0.16, respectively; the ventricular CSF to plasma AUC ratio was 1.18 ± 0.10 and 1.30 ± 0.13, respectively. To study the effect of gefitinib on topotecan CNS penetration, 200 mg/kg gefitinib was administered orally 1 hour before 4 mg/kg topotecan i.v. The brain ECF to plasma AUC ratio of unbound topotecan lactone increased by 1.6-fold to 0.35 ± 0.04, which was significantly different from the ratio without gefitinib (P < 0.05). The ventricular CSF to plasma AUC ratio significantly decreased to 0.98 ± 0.05 (P < 0.05). Breast cancer resistance protein 1 (Bcrp1), an efficient topotecan transporter, was detected at the apical aspect of the choroid plexus in FVB mice. In conclusion, topotecan brain ECF penetration was lower compared with ventricular CSF penetration. Gefitinib increased topotecan brain ECF penetration but decreased the ventricular CSF penetration. These results are consistent with the possibility that expression of Bcrp1 and P-glycoprotein at the apical side of the choroid plexus facilitates an influx transport mechanism across the blood-cerebrospinal fluid barrier, resulting in high topotecan CSF penetration. (Cancer Res 2006; 66(23): 11305-13) |
| Databáze: | OpenAIRE |
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