Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor

Yanli Zhuang, Charles H. Fraga, K. Elaine Hubbard, Nikolaus Hagedorn, John C. Panetta, Christopher M. Waters, Clinton F. Stewart

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11305-11313
Number of pages9
JournalCancer Research
Volume66
Issue number23
DOIs
StatePublished - Dec 1 2006

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Topotecan
Protein-Tyrosine Kinases
Central Nervous System
Cerebrospinal Fluid
Extracellular Fluid
Brain
Area Under Curve
BRCA1 Protein
Choroid Plexus
ATP-Binding Cassette Transporters
Lactones
P-Glycoprotein

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Zhuang, Y., Fraga, C. H., Hubbard, K. E., Hagedorn, N., Panetta, J. C., Waters, C. M., & Stewart, C. F. (2006). Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Research, 66(23), 11305-11313. https://doi.org/10.1158/0008-5472.CAN-06-0929

Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. / Zhuang, Yanli; Fraga, Charles H.; Hubbard, K. Elaine; Hagedorn, Nikolaus; Panetta, John C.; Waters, Christopher M.; Stewart, Clinton F.

In: Cancer Research, Vol. 66, No. 23, 01.12.2006, p. 11305-11313.

Research output: Contribution to journalArticle

Zhuang, Y, Fraga, CH, Hubbard, KE, Hagedorn, N, Panetta, JC, Waters, CM & Stewart, CF 2006, 'Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor', Cancer Research, vol. 66, no. 23, pp. 11305-11313. https://doi.org/10.1158/0008-5472.CAN-06-0929
Zhuang Y, Fraga CH, Hubbard KE, Hagedorn N, Panetta JC, Waters CM et al. Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Research. 2006 Dec 1;66(23):11305-11313. https://doi.org/10.1158/0008-5472.CAN-06-0929
Zhuang, Yanli ; Fraga, Charles H. ; Hubbard, K. Elaine ; Hagedorn, Nikolaus ; Panetta, John C. ; Waters, Christopher M. ; Stewart, Clinton F. / Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. In: Cancer Research. 2006 ; Vol. 66, No. 23. pp. 11305-11313.
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