Thymidylate synthetase - a target enzyme in cancer chemotherapy.

Since their introduction (Heidelberger et al., 1957), the fluorinated pyrimidines and their nucleosides have been widely used as biochemical tools for the elucidation of a number of problems encountered in cell biology and molecular biology. Of more practical importance, however, has been their extensive use as drugs for the palliative treatment of patients suffering from disseminated cancer. One of the compounds is now clinically useful in the curative treatment of herpes simplex viral infections of the eye. Although these compounds have generated an enormous literature, this chapter will deal primarily with a review of the major pharmacological and biochemical effects of these compounds; the coverage of the literature, by necessity, will focus only on key references that are germane to the topics being described. Several reviews of this topic have appeared elsewhere (Heidelberger and Ansfield, 1963; Heidelberger, 1965, 1966, 1967, 1969, 1970, 1973; Mandel, 1969; Carter, 1970).

Fluorinated Pyrimidines and Their Nucleosides

Since the discovery of aspirin and indomethacin as prostaglandin synthesis inhibitors in 1971 (1), within a short span of five years, literally hundreds of chemical structures have been reported as inhibitors of the prostaglandin synthetase system. These compounds, either as therapeutic agents or as research tools, have become a new class of pharmacological agents. Standard drugs such as indomethacin and aspirin, have been used widely and effectively in delineating the involvement of prostaglandins in various biological phenomena. The general correlation of PG synthetase inhibitory activity and antiinflammatory property in many cases has stimulated an active search for new synthetase inhibitors as potential antiarthritic agents. Recently, notable advances were made in several aspects, which not only facilitated the search for new inhibitors, but also suggested possible directions for further improvements. In this communication some notable chemical features of PG synthetase inhibitors will be reviewed briefly. Some of our findings with two new antiarthritic drugs, sulindac and diflunisal, will be highlighted to illustrate the influence of chemical and pharmacokinetic properties on the safety and selectivity of PG synthetase inhibitors.

Prostaglandin Synthetase Inhibitors I

Little evidence exists for stored prostaglandins in tissues (Jouvenaz, Nugteren, Beerthuis and Van Dorp, 1970) and a capacity of a tissue to release prostaglandins seems to reflect principally the capacity for biosynthesis of these compounds. Since prostaglandins represent a diverse family of oxygenated derivatives formed from certain polyunsaturated fatty acids, the 
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Fig. 3.1
Formation and degradation of prostaglandins.

biosynthesis of prostaglandins consists of many steps that involve a variety of different enzymes and cofactors. Inhibition of prostaglandin synthesis may thus occur by blocking any of the several processes that are involved. A brief summary of some of the metabolic events leading to the different prostaglandins is given in Figure 3.1. Because of the diversity of these processes and the stimuli and mediators that appear to modify these reactions it is expected that a wide variety of chemical agents will diminish the formation of prostaglandins in vivo. We will indicate some of the events of prostaglandin biosynthesis known to be influenced by chemical agents, and will suggest a logical framework for comparing the relative inhibitory activity of these different agents.

Inhibition of Prostaglandin Biosynthesis

Fluorinated pyrimidines as tight-binding inhibitors of thymidylate synthetase

Inhibitory effects of aspirin and indomethacin on the biosynthesis of PGE2 and PGF2α

The article describes the structure and mechanism of a Very Early Warning System (VEWS) which was devel-oped as a tool for the early recognition and transfer of new technology, affecting both present and future R&D activities in the pharmaceutical sector The VEWS de-scribed is concerned with the collection, interpretation, analysis, and exploitation of new data from the world-wide scientific and patent literature, scientific meetings, government reports, and personal communications Sys-tems activities are grouped into four phases: data acquisition, data expansion, critical analysis, and data exploitation Iterative processing of an expanding com-puterized data base is a key feature of the system

Marc Julius

Papers

Inhibitory effects of aspirin and indomethacin on the biosynthesis of PGE2 and PGF2α

A very early warning system for the rapid identification and transfer of new technology