Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas.

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Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF

Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas.

Cancer Res. 2010 Jun 1;70(11):4499-508. doi: 10.1158/0008-5472.CAN-09-4264. Epub 2010 May 11.

PubMed ID

20460504 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Topotecan	ATP-dependent translocase ABCB1	Protein	Humans	Unknown	Substrate	Details
Topotecan	Broad substrate specificity ATP-binding cassette transporter ABCG2	Protein	Humans	Unknown	Substrate	Details