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.

Folate pathways are essential in metabolism and macromolecule synthesis. Antifolate drugs that are largely transported via a high capacity folate transporter (i.e. the reduced-folate carrier) and inhibit folate-dependent enzymes include the dihydrofolate reductase inhibitor, methotrexate, and the thymidylate synthase inhibitors, raltitrexed and pemetrexed. Major advances in folate research made within the last decade include (i) the approval of pemetrexed for the treatment of lung cancer and mesothelioma, and (ii) the demonstration that cell membrane-anchored folate receptors (FR) are exploitable for cancer and inflammatory disease management. FRs are not widely distributed in normal tissues, except on some luminal surfaces; however, they are accessible to systemically administered agents when expressed on many cancers as well as on activated macrophages involved in various inflammatory diseases. High affinity folate-radioisotope conjugates have been developed for imaging pathogenic FR-positive diseases, including cancer. Since the FR transports folates via a low capacity but high affinity endocytic pathway, a variety of FR-targeted antifolate drugs and folate conjugates bearing a wide range of payloads (including cytotoxic drugs) are currently being developed which exploit this property. The FR is also being utilized in immunotherapy approaches for the treatment of overexpressing cancers.

Folate pathways are essential in metabolism and macromolecule synthesis. Antifolate drugs that are largely transported via a high capacity folate transporter (i.e. the reduced-folate carrier) and inhibit folate-dependent enzymes include the dihydrofolate reductase inhibitor, methotrexate, and the thymidylate synthase inhibitors, raltitrexed and pemetrexed. Major advances in folate research made within the last decade include (i) the approval of pemetrexed for the treatment of lung cancer and mesothelioma, and (ii) the demonstration that cell membrane-anchored folate receptors (FR) are exploitable for cancer and inflammatory disease management. FRs are not widely distributed in normal tissues, except on some luminal surfaces; however, they are accessible to systemically administered agents when expressed on many cancers as well as on activated macrophages involved in various inflammatory diseases. High affinity folate-radioisotope conjugates have been developed for imaging pathogenic FR-positive diseases, including cancer. Since the FR transports folates via a low capacity but high affinity endocytic pathway, a variety of FR-targeted antifolate drugs and folate conjugates bearing a wide range of payloads (including cytotoxic drugs) are currently being developed which exploit this property. The FR is also being utilized in immunotherapy approaches for the treatment of overexpressing cancers.

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.