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Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas.

Abstract
Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate of the ATP-binding cassette (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 (P(tumor)) of U87 was 0.96 +/- 0.25 (n = 7) compared with that of contralateral brain (P(contralateral), 0.42 +/- 0.11, n = 5; P = 0.001). In MT330 tumors, P(tumor) (0.78 +/- 0.26, n = 6) and P(contralateral) (0.42 +/- 0.11, n = 5) also differed significantly (P = 0.013). Because both tumor models had disrupted blood-brain barriers and similar P(tumor) values, we used U87 and a steady-state drug administration approach to characterize the effect of gefitinib on topotecan P(tumor). At equivalent plasma topotecan exposures, we found that P(tumor) after gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound topotecan in tumor (V(u,tumor)) and found that 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 central nervous system drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer drug distribution within a tumor.
AuthorsAngel M Carcaboso, Mohamed A Elmeliegy, Jun Shen, Stephen J Juel, Ziwei M Zhang, Christopher Calabrese, Lorraine Tracey, Christopher M Waters, Clinton F Stewart
JournalCancer research (Cancer Res) Vol. 70 Issue 11 Pg. 4499-508 (Jun 01 2010) ISSN: 1538-7445 [Electronic] United States
PMID20460504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
CopyrightCopyright 2010 AACR.
Chemical References
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • Topotecan
  • Protein-Tyrosine Kinases
  • Gefitinib
Topics
  • ATP-Binding Cassette Transporters (metabolism)
  • Animals
  • Antineoplastic Agents (pharmacokinetics, pharmacology)
  • Blood-Brain Barrier (drug effects, metabolism, pathology)
  • Brain Neoplasms (blood supply, drug therapy, metabolism, pathology)
  • Cell Line, Tumor
  • Drug Synergism
  • Gefitinib
  • Glioma (blood supply, drug therapy, metabolism, pathology)
  • Humans
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic (metabolism, pathology)
  • Protein Kinase Inhibitors (pharmacology)
  • Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
  • Quinazolines (pharmacology)
  • Topotecan (pharmacokinetics, pharmacology)
  • Xenograft Model Antitumor Assays

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