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Topoisomerase I inhibitors in the treatment of gastrointestinal cancer: from intravenous to oral administration.

Abstract：

:This article reviews the current status of the topoisomerase I (top I) inhibitors in the treatment of gastrointestinal (GI) malignancies. We focus on oral drug administration, the mode of administration that is generally preferred by patients with cancer. However, the great majority of the studies have been performed with intravenous (I.V.) administration. The most extensively investigated GI malignancy in phase I/II studies is colorectal cancer (CRC), for which I.V. irinotecan is currently approved in the United States and Europe. We discuss the activity and efficacy of irinotecan as a single agent in CRC and in combination regimens. Also, results obtained with monotherapy and in combination treatment in other GI malignancies such as esophageal, gastric, and pancreatic cancer are discussed. Few phase I studies have been performed with oral irinotecan and its clinical activity has not yet been fully determined. Several top I inhibitors are discussed, including topotecan, 9-aminocamptothecin, rubitecan, exatecan, and lurtotecan. None of these agents, given orally or intravenously, have shown activity in CRC similar to that of I.V. irinotecan. However, several agents show promising results in other GI malignancies, eg, rubitecan and exatecan in pancreatic cancer. A complicating factor in the oral administration of the top I inhibitors is the often encountered low and variable oral bioavailability. This can partly be explained by the high affinity for the drug efflux pumps BCRP (ABCG2) and P-glycoprotein, which are highly expressed in the epithelial apical membrane of the GI tract. A novel approach to improve the oral bioavailability of the top I inhibitors by temporary blockade of the drug transporter BCRP is described.

journal_name

Clin Colorectal Cancer

journal_title

Clinical colorectal cancer

authors

Kuppens IE,Beijnen J,Schellens JH

doi

10.3816/ccc.2004.n.017

keywords:

subject

Has Abstract

pub_date

2004-09-01 00:00:00

pages

163-80

issue

3

eissn

1533-0028

issn

1938-0674

pii

S1533-0028(11)70114-1

journal_volume

4

pub_type

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