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.
1. Heidelberger C, Chanakari NK, Danenberg PV, et al:
Fluorinated pyrimidines: A new class of tumor inhibitory compounds. Nature