The fluorinated pyrimidines, in particular 5-fluorouracil (5-FU), are among the oldest cytotoxic agents still in broad use today. To some degree, this continued use of 5-FU is a bit of an embarrassment to those of us who spend considerable amounts of time trying to develop something better with which to replace it. On the other hand, the ongoing and widespread use of 5-FU and related agents underscores the considerable scientific achievement the development of 5-FU represented. The magnitude of this achievement is perhaps not fully appreciated until one considers the difficulty encountered in trying to develop an agent to surpass its efficacy.
First described by Heidelberger et al in 1957, 5-FU was what is now termed "a rationally designed drug," based on the observation that the uptake of uracil was greater in tumor cells than in nonmalignant cells. Over the past 4 decades, numerous investigators have explored and characterized the pathways by which 5-FU disrupts cellular replication. Based on this scientific understanding, multiple modulation strategies have been developed to exploit this knowledge and thus increase the clinical efficacy of 5-FU. These efforts have met with variable degrees of success. Overall, however, while response rates have improved somewhat and modest survival benefits in the adjuvant setting have been achieved for some diseases, little if any survival advantage in patients with advanced disease has been achieved. Further, severe, sometimes life-threatening toxicities may still be encountered.
Questions Still to Be Answered
Where, then, do we go from here with the fluorinated pyrimidines? Have we pushed the limits of our understanding of biomodulation, or can further modifications in how we administer these agents make a real difference in efficacy? Can we, through molecular genetic characterization of the tumor, identify those patients who are most or least likely to benefit from 5-FU and tailor treatment decisions accordingly? What are the benefits and the drawbacks to the orally-administered analogues of 5-FU that are entering clinical practice? Finally with numerous new agents entering clinical practice, how can the older and newer fluorinated pyrimidines be most effectively incorporated into combination regimens?
These and other pertinent questions were addressed by the participants of this symposium. The presentations and the discussion that follows in this publication highlight the importance and the complexity of these issues. The questions are far easier to ask and explore than to definitively answer. Nevertheless, it is clear that we continue to make considerable progress in our understanding of these issues, and with this progress comes new treatment options and new hope for our patients.