Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas.
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.
Carcaboso
Angel M
AM
Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-2794, USA.
Elmeliegy
Mohamed A
MA
Shen
Jun
J
Juel
Stephen J
SJ
Zhang
Ziwei M
ZM
Calabrese
Christopher
C
Tracey
Lorraine
L
Waters
Christopher M
CM
Stewart
Clinton F
CF
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000077156:Gefitinib; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D019772:Topotecan / Q000493:pharmacokinetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019772:Topotecan; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib
Cancer Res. 2006 May 1;66(9):4802-7
16651435
Cancer Chemother Pharmacol. 1995;36(5):393-403
7634381
J Neurooncol. 2007 Apr;82(2):175-6
17008949
Mol Cell Biol. 2004 Sep;24(17):7612-21
15314169
Cancer Chemother Pharmacol. 1994;34(2):171-4
8194169
Nat Rev Cancer. 2002 Jan;2(1):48-58
11902585
J Pharm Sci. 2004 Sep;93(9):2284-95
15295789
Cancer Res. 2001 Jul 15;61(14):5491-8
11454697
Cancer Res. 2005 Aug 1;65(15):6943-9
16061679
Curr Protoc Neurosci. 2009 Apr;Chapter 7:Unit7.1
19340812
Cancer Res. 2003 Aug 15;63(16):5114-7
12941842
Cancer Res. 2008 Oct 1;68(19):7905-14
18829547
Pharm Res. 2008 Aug;25(8):1737-50
18058202
Cancer Res. 2004 Oct 15;64(20):7491-9
15492275
Cancer Chemother Pharmacol. 2006 Nov;58(5):594-600
16520985
Invest New Drugs. 2008 Jun;26(3):205-13
17943230
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1977-82
19174516
Cancer Res. 1999 Sep 15;59(18):4559-63
10493507
J Clin Oncol. 2007 Oct 20;25(30):4722-9
17947719
Int J Cancer. 1998 Dec 18;79(6):640-4
9842975
J Clin Oncol. 2009 Sep 20;27(27):4599-604
19687340
Am J Pathol. 1996 Sep;149(3):853-8
8780389
J Child Neurol. 2008 Oct;23(10):1214-20
18952588
Clin Cancer Res. 2007 Nov 1;13(21):6440-9
17975156
Mol Cancer Ther. 2009 Jun;8(6):1438-47
19509243
Neurosurgery. 2006 Feb;58(2):365-72; discussion 365-72
16462491
Cancer Res. 2009 Jul 15;69(14):5885-92
19567673
Nat Rev Neurosci. 2005 Aug;6(8):591-602
16025095
Cancer Res. 2006 Dec 1;66(23):11305-13
17145877
Int J Cancer. 2008 May 1;122(9):1981-6
18081012
Endothelium. 2002;9(2):83-7
12200959
J Pediatr Surg. 2007 Jul;42(7):1172-9
17618876
Cancer Res. 2004 Apr 1;64(7):2333-7
15059881
Cancer Res. 2009 Jul 1;69(13):5296-300
19549889
J Clin Invest. 2002 Nov;110(9):1309-18
12417570
Cancer Res. 2007 Nov 15;67(22):11012-20
18006847
J Natl Cancer Inst. 2007 Oct 3;99(19):1441-54
17895480
J Neurooncol. 2009 Jan;91(1):51-8
18787762
Pharm Res. 1996 Mar;13(3):398-403
8692732
J Neurooncol. 2006 Apr;77(2):193-8
16314955
N Engl J Med. 2008 Jul 31;359(5):492-507
18669428
Clin Cancer Res. 2008 Dec 1;14(23):7900-8
19047120
Biomed Chromatogr. 2009 Jul;23(7):707-13
19277971
Eur J Cancer. 2000 Aug;36(12):1578-84
10930807
J Neurooncol. 2007 Nov;85(2):133-48
17874037
Glia. 2009 Sep;57(12):1306-15
19191326
J Nucl Med. 2005 Nov;46(11):1835-41
16269597