Antifolates are an important class of anticancer drugs originally
developed as anti leu- kemic agents, but now used, usually in
combination with other drugs, for the treatment of a wide range of
tumors, notably carcinomas of the head and neck, breast, germ cell
tumors, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and
osteogenic sar- comas. 5-Fluorouracil and its prodrugs also target, in
part, the folate-dependent enzyme, thymidylate synthase. Furthermore,
folate supplementation in the form of leucovorin, modulates
5-fluororuacil activity. 5-Fluorouracil is widely used in the treatment
of colorectal and gastric cancer and in combination for other solid
tumors such as breast and head and neck cancers. Ongoing clinical trials
with the newer antifolates suggest that the range of solid tumors where
these agents will be of use may broaden further. Half a century ago,
interesting scientific and clinical discoveries suggested that folie
acid was a vitamin involved in vital cellular metabolic processes. The
folate analogs, aminopterin and methotrexate, were synthesized by the
American Cyanamid Company in an attempt to interfere with these
processes and were shown to have anticancer activity by Farber and his
colleagues. Hence, the principle of antimetabolite therapy for the
treatment of cancer was established. Biomedical research over the
following years led to a deeper understanding of the complex biochemical
pharmacology of folates and antifolates. Selective antimicrobial agents
were discovered, but more tumor-selective anticancer agents did not
immediately emerge.
