Capecitabine Preclinical Studies: From Discovery to Translational Research

Abstract

The most desirable formulation for anti-cancer drugs requiring frequent administration would be a tablet, similar to the treatment of many other diseases. Oral treatment would not only reduce medical treatment costs but also allow cancer patients to spend less time in hospital and more time with their family and friends. In fact, cancer patients prefer oral treatment if it is as effective as parenteral treatment [1]. In addition, a tablet is most appropriate for the long-term frequent treatment of cancer cells. Although many cytotoxic drugs effectively inhibit tumor cells only in particular processes of the cell cycle, such as the S phase and M phase, not all tumor cells are present in the tissues during such processes. In order to be effective, cytotoxic drugs should be administered continuously over a period of time which is longer than one cell cycle. However, the daily administration of cytotoxic drugs is limited because of the accumulation of non-tumor-selective toxicity. When given orally, cytotoxic drugs generally lead to high concentrations of the drug, predominantly at the local sites, such as the intestine and liver, and this results in treatmentassociated adverse effects on these organs. On the other hand, oral doses of cytotoxic drugs are generally larger than parenteral doses, because drugs given orally are often subjected to first-pass metabolic effects in the intestinal tract and liver. Unfortunately, a reduction in dose to spare such local organ toxicity results in an insufficient efficacy compared with that of parenteral administration.In 1986, the present authors commenced studies into the design and synthesis of orally available cytotoxic compounds with high tumor selective activity and low myelotoxicity or intestinal toxicity, and which therefore would be safe for daily oral treatment over prolonged periods of time in the comfort of the home. The strategy employed, specifically identifying new cytotoxic compounds with high tumor-selective action, included the design and synthesis of a prodrug that, from oral administration, generates an active cytotoxic component from enzymes

Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry

“…Two prodrugs of 1 , Capecitabine ( 6 ) and Galocitabine ( 39 ), are 5-fl uorocytidine derivatives. Both the compounds were developed by Hoffman La Roche; whereas Capecitabine was launched in 1998, Galocitabine was terminated at Phase II clinical trials [ 47 ]. Both the compounds are close analogues as well as prodrugs of Doxifl uridine ( 5 ), which was used as the lead compound in their design.…”

Synthesis and Biological Properties of 5-(1H-1,2,3-Triazol-4-yl)isoxazolidines: A New Class of C-Nucleosides

“…Structural modification of natural N -nucleosides on either the sugar unit or the nucleobase has led to the discovery of a variety of new therapeutic agents, which includes antiviral and anticancer agents [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. In this context, the family of C -nucleosides constitutes a group of molecules characterized by the link of the sugar unit to a carbon atom of the pyrimidine/purine nucleobase: some of these compounds have been reported to exhibit significant antibacterial, antiviral and antitumoral activities [ 10 ].…”