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Integrative Medicine
> Topotecan
/ ZD1839
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Cancer Research 66, 11305-11313, December 1, 2006. doi:
10.1158/0008-5472.CAN-06-0929
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Abstract |
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Topotecan Central Nervous System
Penetration Is Altered by a Tyrosine Kinase Inhibitor
Yanli Zhuang1,
Charles H. Fraga1,
K. Elaine Hubbard1,
Nikolaus Hagedorn1,
John C. Panetta1,
Christopher M. Waters2
and Clinton F. Stewart1
1Department of
Pharmaceutical Sciences, St. Jude Children's Research Hospital and 2Department
of Physiology, College of Medicine, University of Tennessee Health
Science Center, Memphis, Tennessee -- Requests for reprints: Clinton
F. Stewart, Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105.
Phone: 901-495-3365; Fax: 901-525-6869; E-mail: clinton.stewart@stjude.org.
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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.
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© 2006 American Association for Cancer Research
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Abstract |
Reprint
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