Gefitinib enhances the antitumor activity of CPT-11 in vitro and in vivo by inhibiting ABCG2 but not ABCB1: a new clue to circumvent gastrointestinal toxicity risk

Yutaka Inoue; Yoji Ikegami; Kazumi Sano; Toshihiro Suzuki; Hisahiro Yoshida; Yoichi Nakamura; Hiroshi Nakagawa; Toshihisa Ishikawa

doi:10.1159/000357772

Gefitinib enhances the antitumor activity of CPT-11 in vitro and in vivo by inhibiting ABCG2 but not ABCB1: a new clue to circumvent gastrointestinal toxicity risk

Chemotherapy. 2013;59(4):260-72. doi: 10.1159/000357772. Epub 2014 Jan 17.

Authors

Yutaka Inoue¹, Yoji Ikegami, Kazumi Sano, Toshihiro Suzuki, Hisahiro Yoshida, Yoichi Nakamura, Hiroshi Nakagawa, Toshihisa Ishikawa

Affiliation

¹ Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, Tokyo, Japan.

PMID: 24457609
DOI: 10.1159/000357772

Abstract

Background: Despite the potent antitumor activity of CPT-11, late-onset diarrhea owing to enterohepatic circulation of SN-38 is a critical issue.

Methods: We aimed to evaluate the inhibitory potency of gefitinib against the ABCB1- or ABCG2-mediated excretion of CPT-11 and its active metabolite SN-38 in vitro and in vivo.

Results: Gefitinib dose-dependently enhanced the antiproliferation activity of SN-38 in vitro by inhibiting ABCG2. The inhibitory effect of gefitinib on ABCB1 was marginal. When both CPT-11 and gefitinib were administered orally to nude mice bearing human lung cancer PC-6 cells, tumor growth was markedly suppressed. By gefitinib coadministration, the lactone forms of both CPT-11 and SN-38 in the tumor tissue increased more than 2-fold.

Conclusions: Gefitinib significantly enhances the antitumor efficacy of CPT-11 and its tumor distribution in vivo. Coadministration of gefitinib may provide a new means to reduce the dose of CPT-11 and to circumvent the gastrointestinal toxicity risk.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / antagonists & inhibitors
ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism*
Administration, Oral
Animals
Antineoplastic Agents / adverse effects
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Camptothecin / adverse effects
Camptothecin / analogs & derivatives*
Camptothecin / pharmacology
Camptothecin / therapeutic use
Cell Line, Tumor
Cell Survival / drug effects
Diarrhea / etiology
Drug Synergism
Drug Therapy, Combination
Female
Gefitinib
HEK293 Cells
Humans
Irinotecan
Lung Neoplasms / drug therapy
Lung Neoplasms / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Quinazolines / adverse effects
Quinazolines / pharmacology*
Quinazolines / therapeutic use
RNA, Messenger / metabolism
Transplantation, Heterologous

Substances

ABCB1 protein, human
ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Antineoplastic Agents
Neoplasm Proteins
Quinazolines
RNA, Messenger
Irinotecan
Gefitinib
Camptothecin