OSI-7904L is a liposomal formulation of the highly specific, noncompetitive thymidylate synthase inhibitor OSI-7904 (also known as GW1843, BW1843U89, and GS7904). The liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent antifolate compound. This drug was studied in phase II clinical trial in patients to treat head and neck cancer, gastroesophageal adenocarcinoma and advanced biliary cancer, but these studies were discontinued. As an example in case of OSI-7904L, was revealed that its activity was below a level of clinical relevance in advanced biliary tract cancer, providing only a small degree of disease stabilization.

5-Fluoro-2-deoxycytidine is a fluorinated pyrimidine analog antimetabolite with potential antineoplastic activity. As a prodrug, 5-fluoro-2-deoxycytidine is converted by intracellular deaminases to the cytotoxic agent 5-fluorouracil (5-FU). 5-FU is subsequently metabolized to active metabolites including 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP binds to and inhibits thymidylate synthase, thereby reducing the production of thymidine monophosphate, which leads to depletion of thymidine triphosphate and the inhibition of DNA synthesis and cell division. FUTP competes with uridine triphosphate (UTP) for incorporation into the RNA strand, which results in the inhibition of RNA and protein synthesis and cell proliferation. 5-Fluoro-2-deoxycytidine undergoing trials to test its effectiveness in treating cancer that has not responded to standard therapies.

Plevitrexed is a rationally designed, orally bioavailable, nonpolyglutamatable quinazoline antifolate that is a selective inhibitor of thymidylate synthase with potent antineoplastic activity and the ability to overcome antifolate resistance due to decreased folylpolyglutamate synthetase activity. It also features a lower toxicity than polyglutamatable thymidylate synthase inhibitors, presumably due to a lesser cellular retention. Plevitrexed is primarily transported into the cells via reduced folate carrier and selectively binds to the folate-binding site of thymidylate synthase with high affinity. Plevitrexed was assessed and in preclinical studies against a panel of human ovarian cancer cell lines and in several phase II clinical studies for the treatment of various solid cancers including colorectal, gastric, pancreatic and ovarian cancer. The combination of plevitrexed and carboplatin is well tolerated with no significant pharmacokinetic interaction between the two drugs - antitumor activity in platinum-pretreated gynecological malignancy was demonstrated.

Torcitabine is the beta-L-enantiomer of the natural nucleoside D-cytidine. The drug was under development as an antiviral agent for the treatment of chronic hepatitis B virus infection. Torcitabine has poor oral bioavailability, but its 3’,5’-derivative ester (val-L-dC) and the 3’-monovaline ester, valtorcitabine dihydrochloride, have excellent oral bioavailability and consequently the torcitabine prodrug, valtorcitabine, has replaced torcitabine in clinical development. Torcitabine is active against hepadnaviruses, specifically human hepatitis B virus (HBV), duck hepatitis virus (DHBV) and woodchuck hepatitis virus (WHV). Torcitabine triphosphate is a selective inhibitor of the polymerase enzyme of HBV.

KETOTREXATE is an antifolate developed to overcome methotrexate (MTX) resistance. However, it demonstrated such potential only in MTX-resistant sensitive L1210/FR8 leukemia cells and its clinical development was discontinued. Unlike MTX, KETOTREXATE exhibited minimal inhibition of purified dihydrofolate reductase, which implies that it does not act as a classical antifolate.

Lodenosine is the experimental HIV reverse transcriptase inhibitor. It was designed as a chemically and enzymatically stable anti-AIDS drug. A phase II trial of the nucleoside analog lodenosine was suspended after one participant died and others showed signs of liver or kidney damage.

Eniluracil (5-ethynyluracil, GW 776, 776C85) is a potent irreversible inhibitor of dihydropyrimidine dehydrogenase, the first enzyme in the catabolic pathway of 5-fluorouracil (5-FU), the most widely used drug in cancer chemotherapy. Eniluracil increases the oral bioavailability of 5-FU to 100%, facilitating uniform absorption and predictable toxicity. Eniluracil was being developed as a novel modulator of 5-FU for the treatment of cancer.

Galocitabine is an orally available 5-fluorouracil (5-FU) prodrug with potential antineoplastic activity. Upon administration, galocitabine is converted to 5’-deoxy-fluorocytidine (5’-DFCR) by acylamidase in the liver and is then converted to 5’-DFUR by cytidine deaminase. Efficient conversion of galocitabine to 5-FU is necessary for galocitabine to have a therapeutic effect. 5-FU is further metabolized into other cytotoxic metabolites that interfere with RNA and DNA synthesis via inhibition of thymidylate synthase. As a result, this agent eventually inhibits tumor cell growth.

Navuridine (AzddU) is a nucleoside analogue which demonstrated significant anti-HIV activity and low toxicity in preclinical studies. The drug was originally developed by University of Georgia. Navuridine is a dideoxyuridine inhibitor of HIV reverse transcriptase that is related to zidovudine. Navuridine exhibits a relatively short half-life and incomplete oral bioavailability and has not been developed into a clinical drug.

Metoprine is a diaminopyrimidine folate antagonist with potential antineoplastic activity. Metoprine inhibits dihydrofolate reductase, resulting in decreased cellular folate metabolism and cell growth. Metoprine shows potent in vitro antitumor activity against several experimental tumors including methotrexate-resistant tumors. Metoprine inhibits the enzyme dihydrofolate reductase, much less effectively than methotrexate but it also inhibits histamine-N-methyltransferase, resulting in decreased histamine catabolism. S phase cells are most sensitive, whilst cells in G2 and M are least sensitive to the lethal effects of Metoprine, and a prolonged exposure to a high Metoprine concentration produces maximum cytotoxic effects. After oral administration, Metoprine has a widespread distribution and concentration in all tissues examined with the highest tissue/plasma ratios found in brain, lung, pancreas, and skin. Phase I and early Phase II clinical trials in various centers have shown activity in hypernephroma, epidermoid carcinoma arising in bronchus or head and neck, central nervous system leukemia, malignant melanoma, and mycosis fungicides. Metoprine had been in some phase II clinical trials but further studies were discontinued due to CNS and hematological toxicity.