NDLI: Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas

Content Provider	PubMed Central
Author	Carcaboso, Angel M. Elmeliegy, Mohamed A. Shen, Jun Juel, Stephen J. Zhang, Ziwei M. Calabrese, Christopher Tracey, Lorraine Waters, Christopher M. Stewart, Clinton F.
Abstract	Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate of the ABC transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect of modulating these transporters on topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human gliomas (U87 and MT330), and assessed topotecan tumor ECF (tECF) penetration and the effect of gefitinib on topotecan tECF penetration and intratumor topotecan distribution. We found that topotecan penetration (Ptumor ) of U87 was 0.96 ± 0.25, n=7, compared with that of contralateral brain (Pcontralateral , 0.42 ± 0.11, n=5; P = 0.001). In MT330 tumors, Ptumor (0.78 ± 0.26, n=6) and Pcontralateral (0.42 ± 0.11, n=5) also differed significantly (P = 0.013). Since both tumor models had disrupted blood brain barriers and similar Ptumor values, we used U87 and a steady-state drug administration approach to characterize the effect of gefitinib on topotecan Ptumor . At equivalent plasma topotecan exposures, we found that Ptumor after gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound topotecan in tumor (Vu,tumor ) and found it was significantly higher in groups receiving gefitinib, implying that gefitinib administration leads to a greater proportion of intracellular topotecan. Our results provide crucial insights into the role that transporters play in CNS drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer drug distribution within a tumor.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-4264
Ending Page	4508
Page Count	10
Starting Page	4499
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	11
Volume Number	70
Language	English
Publisher Date	2010-06-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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