Special Issue on "5-Fluorouracil" of the Molecules journal

Introduction

Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains one of the most important anticancer agents. In 5-FU, the hydrogen atom at the 5-position of uracil is replaced by a fluorine atom and the molecule was designed to occupy the active sites of enzyme targets, thereby blocking metabolism in malignant cells. Although this antimetabolite is toxic, its efficacy makes it one of the most widely used agents against solid tumors. Numerous reports by the scientific community have been devoted to 5-FU, covering a wide range of topics: preparation of innovative formulations, synthesis of 5-FU derivatives, mechanism of action studies, etc. This special issue of Molecules aims to provide an overview of the current knowledge on this important chemotherapeutic agent, as well as focus on current strategies to improve therapeutic effectiveness of this drug in the treatment of advanced disease.

Guest Editor for this Special Issue
Dr Francesco Puoci

Review manuscripts: Before writing their manuscripts, potential authors of review articles should forward the title and a short abstract to the Guest Editor. The Guest Editor will then provide feedback on the suitability of the topic upon consultation with other editors and/or members of the Editorial Board. Authors are encouraged to write reviews that provide a critical appraisal of areas of 5-fluorouracil research.

Ning Zhang ¹, Ying Yin ², Sheng-Jie Xu ² and Wei-Shan Chen ^1,*
1 Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, #88 Jiefang Road, Hangzhou, 310009, P.R. China; E-mail: [email protected]
2 Institute of Clinical Research, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, #3 East Qingchun Road, Hangzhou, 310016, P.R. China; E-mails: [email protected], [email protected]
* Author to whom correspondence should be addressed; E-mail: [email protected]
Received: 18 June 2008; in revised form: 1 July 2008 / Accepted: 15 July 2008 / Published: 5 August 2008
Review: 5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies
Molecules 2008, 13, 1551-1569 (PDF format 214 K); DOI: 10.3390/molecules13081551

Georgios V. Koukourakis ^1,*, Vassilios Kouloulias ¹, Michael J. Koukourakis ², Georgios A. Zacharias ³, Haralabos Zabatis ⁴, John Kouvaris ⁵
1 Attikon University Hospital of Athens, 2nd Radiology Department, Radiation Therapy Unit, Medical School of Athens, Greece; Emails: [email protected] (Koukourakis); [email protected] (Kouloulias)
2 University Hospital of Thrace, Radiation Therapy Unit, Alexandroupolis, Greece; Email: [email protected]
3 Policlinic of Athens, Section of Pathology, Athens Greece. Email: [email protected]
4 Saint Savvas Anticancer Institute of Athens, 1st Radiation Therapy Unit Athens Greece; Email: [email protected]
5 Aretaieion University Hospital, 1st Radiology Department, Radiation Therapy Unit, Medical School of Athens, Greece; Email: [email protected]
* Author to whom correspondence should be addressed. Email: [email protected].
Received: 30 May 2008; in revised form: 15 August 2008 / Accepted: 25 August 2008 / Published: 27 August 2008
Review: Efficacy of the Oral Fluorouracil Pro-drug Capecitabine in Cancer Treatment: a Review
Molecules 2008, 13, 1897-1922 (PDF format 289 K); DOI: 10.3390/molecules13081897

Manuscript ID: molecules-fluorouracil-05-jp-Nishimoto
Title: Radiation- and photo-induced activation of 5-fluorouracil prodrugs as a strategy for selective treatment of solid tumors
Authors: Sei-ichi Nishimoto, Kazuhito Tanabe, Takeo Ito, Hisatsugu Yamada,and Hiroshi Hatta
Corresponding author: Sei-ichi Nishimoto, Ph.D. Professor of Excited-State Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Kyoto 615-8530, Japan
Tel: +81-75-383-2500/FAX: +81-75-383-2501
E-mail: [email protected]
URL: http://www.ehcc.kyoto-u.ac.jp/eh32/home/web-content/index-e.htm
Abstract: Nowadays, 5-fluorouracil (5FU) is widely used as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers, although its clinical application is limited because 5FU shows gastrointestinal and hematological toxicities. A great deal of efforts have been made in the search for prodrugs with functions that are
tumor-selectively delivered and activated to improve the clinical utility of 5FU as an important cancer chemotherapeutic agent. Since UV-light and ionizing radiations can cause chemical reactions in a localized area of the body,their applications into site-specific drug activation and sensitization have been thus developed. In this review, we describe recent progress in
The development of novel 5FU prodrugs that are site-specifically activated by UV-light and ionizing radiations under tumor microenvironments, and discuss chemical mechanisms of the activation.

Manuscript ID: fluorouracil-20080630-Breda-it
Title: A Review of Analytical Methods for the Determination of 5-Flurouracil in Biological Matrices
Authors: Massimo Breda, Simona Barattè
Corresponding author: Massimo Breda, Accelera, Nerviano Medical Sciences, Viale Pasteur 14, 20014 Nerviano, Milan, Italy
E-mail: [email protected]
Abstract: 5-Fluorouracil (5-FU) is a cytostatic agent, which has been widely used in the treatment of various solid tumours for more than 20 years, and is still considered amongst the most active antineoplastic agent in the advanced colorectal cancer and malignancies of head and neck. A large number of non-chromatographic and chromatographic methods for the quantitation of 5-FU, related pro-drugs, and their metabolites in biological matrices have been developed in the last 30 years to support preclinical and clinical studies. In this review the advantages and disadvantages of these analytical methods will be discussed.

Manuscript ID: molecules-fluorouracil-03-Farquharson
Title: Detection of 5-Fluorouricil in Saliva by Surface-Enhanced Raman Spectroscopy
Authors: Stuart Farquharson, Alan Gift, Chetan Shende, Frank Inscore, Beth Ordway, Carl Farquharson and John Murran
Corresponding author: Stuart Farquharson, President & CEO, Real-Time Analyzers, Inc. 362 Industrial Park Rd. (#8) Middletown, CT 06457 860-635-9800, x230
E-mail: [email protected]
Abstract: The ability of surface-enhanced Raman spectroscopy (SERS) to measure 5-fluorouracil (5-FU) in saliva is presented. The approach is based on the ability of Raman spectroscopy to provide a unique spectral signature for virtually every chemical, and the ability of SERS to provide microgram/milliliter sensitivity. A simple sampling method, that employed 1-mm glass capillaries filled with silver-doped sol-gels, was developed to isolate 5-FU from potential interfering chemical components of saliva and simultaneously provide SERS-activity. The method involved treating a 1 milliliter saliva sample with 1 milliliter of acetic acid, drawing 10 microliters of sample into a SERS-active capillary by syringe, and then measuring the SER spectrum. Quality SER spectra were obtained for samples containing as little as 2 micrograms of 5-FU in 1 milliliter saliva. The entire process, the acid pretreatment, extraction and spectral measurement, took less than 5 minutes. The surface-enhanced Raman spectra of 5-fluorouridine and 5-fluoro-2-deoxyuridine, two major metabolites of 5-FU, were also measured and shown to have unique spectral peaks. These measurements suggest that disposable SERS-active capillaries could be used to measure 5-FU and metabolite concentrations in chemotherapy patient saliva, thereby providing metabolic data that would allow regulating dosage. Tentative vibrational mode assignments for 5-FU and its metabolites are also given.
Received: 6 July 2008

Manuscript ID: molecules-fluorouracil-04-es-Arias
Title: Novel Strategies to Improve the Anticancer Action of 5-Fluorouracil by Using Drug Delivery Systems
Author: Jose L. Arias
Corresponding author: Dr. Jose L. Arias, Grupo Investigación Farmacia Práctica (CTS-205), Dept. Farmacia y Tecnología Farmacéutica Facultad de Farmacia, Campus Universitario de Cartuja, s/n, Universidad de Granada, 18071 Granada
Tel.: (+34) 958 24 39 02; Fax: (+34) 958 24 89 58
E-mail: [email protected]
Abstract: Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of the anticancer drug 5-fluorouracil have been devised. The target is always to provide the proper dose of the antitumour agent only at the desired locus of action, thus reducing the unwanted side effects. In this review, the main strategies and the more significant results in the development of 5-fluorouracil carriers for cancer treatment are discussed.

Yasuhiro Tsume ¹, Balvinder S. Vig ², Jing Sun ³, Christopher P. Landowski ⁴, John M. Hilfinger ⁵, Chandrasekharan Ramachandran ¹ and Gordon L. Amidon 1,*
1 Department of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA; E-mails: [email protected]; [email protected]
2 Pharmaceutical Research Institute, Bristol-Myers Squibb Company, New Brunswick, NJ 08502; E-mail: [email protected]
3 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA; Email: [email protected]
4 Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland; E-mail: [email protected]
5 TSRL, Inc. Ann Arbor, Michigan 48108, USA; Email: [email protected]
* Author to whom correspondence should be addressed; E-mail: [email protected]; Phone: +1-734-764-2440; Fax: +1-734-763-6423.
Received: 12 June 2008 / Accepted: 27 June 2008 / Published: 28 June 2008
Article: Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters
Molecules 2008, 13, 1441-1454 (PDF format 132 K); DOI: 10.3390/molecules13071441

Francesco Puoci ^1,*, Francesca Iemma ¹, Giuseppe Cirillo ¹, Nevio Picci ¹, Pietro Matricardi ² and Franco Alhaique ²
1 Dipartimento di Scienze Farmaceutiche, Università della Calabria, Edificio Polifunzionale, Arcavacata di Rende (CS) 87036, Italy
2 Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, University “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy
* Author to whom correspondence should be addressed; email: [email protected]; Tel. (+39) 0984493151, fax (+39) 0984493151
Received: 21 March 2007; in revised form: 13 March 2007 / Accepted: 16 April 2007 / Published: 18 April 2007
Full Paper: Molecularly Imprinted Polymers for 5-Fluorouracil Release in Biological Fluids
Molecules 2007, 12, 805-814 (PDF format 69 K)