Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice

Clinton F. Stewart, Markos Leggas, John D. Schuetz, John C. Panetta, Pamela J. Cheshire, Jennifer Peterson, Najat Daw, Jesse J. Jenkins, Richard Gilbertson, Glen S. Germain, Franklin C. Harwood, Peter J Houghton

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Abstract

As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [14C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.

Original languageEnglish (US)
Pages (from-to)7491-7499
Number of pages9
JournalCancer Research
Volume64
Issue number20
DOIs
StatePublished - Oct 15 2004
Externally publishedYes

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irinotecan
Biological Availability
Heterografts
gefitinib
Camptothecin
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Stewart, C. F., Leggas, M., Schuetz, J. D., Panetta, J. C., Cheshire, P. J., Peterson, J., ... Houghton, P. J. (2004). Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Research, 64(20), 7491-7499. https://doi.org/10.1158/0008-5472.CAN-04-0096

Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. / Stewart, Clinton F.; Leggas, Markos; Schuetz, John D.; Panetta, John C.; Cheshire, Pamela J.; Peterson, Jennifer; Daw, Najat; Jenkins, Jesse J.; Gilbertson, Richard; Germain, Glen S.; Harwood, Franklin C.; Houghton, Peter J.

In: Cancer Research, Vol. 64, No. 20, 15.10.2004, p. 7491-7499.

Research output: Contribution to journalArticle

Stewart, CF, Leggas, M, Schuetz, JD, Panetta, JC, Cheshire, PJ, Peterson, J, Daw, N, Jenkins, JJ, Gilbertson, R, Germain, GS, Harwood, FC & Houghton, PJ 2004, 'Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice', Cancer Research, vol. 64, no. 20, pp. 7491-7499. https://doi.org/10.1158/0008-5472.CAN-04-0096
Stewart CF, Leggas M, Schuetz JD, Panetta JC, Cheshire PJ, Peterson J et al. Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Research. 2004 Oct 15;64(20):7491-7499. https://doi.org/10.1158/0008-5472.CAN-04-0096
Stewart, Clinton F. ; Leggas, Markos ; Schuetz, John D. ; Panetta, John C. ; Cheshire, Pamela J. ; Peterson, Jennifer ; Daw, Najat ; Jenkins, Jesse J. ; Gilbertson, Richard ; Germain, Glen S. ; Harwood, Franklin C. ; Houghton, Peter J. / Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. In: Cancer Research. 2004 ; Vol. 64, No. 20. pp. 7491-7499.
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