Leucovorin is a compound similar to folic acid, which is a necessary vitamin. It has been around and in use for many decades. Leucovorin is a medication frequently used in combination with the chemotherapy drugs fluoruracil and methotrexate. Leucovorin is not a chemotherapy drug itself, however it is used in addition to these chemotherapy drugs to enhance anticancer effects (with fluorouracil) or to help prevent or lessen side effects (with methotrexate). Leucovorin is also used by itself to treat certain anemia problems when folic acid deficiency is present.

Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand. Fluorouracil is used for the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid.

Levoleucovorin is the pharmacologically active isomer of leucovorin or 5-formyl tetrahydrofolic acid, a folate analog . Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “onecarbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme. Fusilev® (levoleucovorin) is approved by FDA for i) rescue after high-dose methotrexate therapy in osteosarcoma, ii) diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists and iii) in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

Folic Acid is a B complex vitamin containing a pteridine moiety linked by a methylene bridge to para-aminobenzoic acid, which is joined by a peptide linkage to glutamic acid. Conjugates of Folic Acid are present in a wide variety of foods, particularly liver, kidneys, yeast and leafy green vegetables. Commercially available Folic Acid is prepared synthetically. Folic Acid occurs as a yellow or yellowish-orange crystalline powder and is very slightly soluble in water and insoluble in alcohol. Aqueous solutions of Folic Acid are heat sensitive and rapidly decompose in the presence of light and/or riboflavin; solutions should be stored in a cool place protected from light. Folic Acid is effective in the treatment of megaloblastic anemias due to a deficiency of Folic Acid (as may be seen in tropical or nontropical sprue) and in anemia of nutritional origin, pregnancy, infancy, or childhood. Folic Acid is relatively nontoxic in man. Rare instances of allergic responses to Folic Acid preparations have been reported and have included erythema, skin rash, itching, general malaise, and respiratory difficulty due to bronchospasm. Endocyte is developing an intravenous (IV) formulation of folic acid, called Neocepri®, which is intended for the diagnosis of positive folate receptor-positive status in patients with ovarian cancer when administered prior to the radioactive medicine, technetium Tc99m Etarfolatide. The benefits of Neocepri® are its ability to reduce the background activity observed on single photon emission computed tomography (SPECT) imaging in most normal, nontarget tissues (e.g. intestines, liver, kidney, spleen), thereby improving the image quality of the scans. The product had been granted orphan drug designation in the EU. Endocyte had filed a conditional marketing authorization application (CMA) with the European Medicines Agency (EMA) for Neocepri®.