Citrovorum factor

Cltrivorum factor (CF), folinic acid, and leuco-vorin are all N-[4[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]-amino]benzoyl]glutamic acid, I, the Leuconostoc citrovorum 8081 growth factor first reported by Sauberlich and Baumann.1 Leucovorin refers to the chemically synthesized material that contains both dL and 1L diastereomers "citrovorum factor" and "folinic acid" generally apply to the biologically synthesized 1L isomer. 

Citrovorum factor has been reported to be stable under severe alkaline conditions by Broquist et al.3s and earlier by Lyman and Prescott.36 Steam-heating for 30 minutes in 0.2N NaOH did not decompose the compound. 

In humans and rats, early investigations showed that large doses of folic acid resulted in increased excretion of a substance that stimulated the growth of P. cerevisiae and that was presumed to be citrovorum factor.45 This response is now also associated with other reduced folates. 

Spies, T. D., Lopez, G. G., Milanes, F., Toca, R. L., Reboredo, A., and Stone, R. E., The response of patients with pernicious anemia, with nutritional macrocytic anemia and with tropical sprue to folinic acid or citrovorum factor. Southern Med. J. 43, 1076-1082 (1950). 

Silverman, M., and Wright, B. E., Microbiological aspects of the diglutamyl derivatives of citrovorum factor and N10-formylfolic acid. J. Bacteriol. 72, 373-377 (1956). 

Excretion of thiamine appears to vary from individual to individual,23 and some other data are available regarding the other better-known B vitamins.24 The differences in the excretion of nicotinic acid-like compounds strongly suggest the existence of individual pattems.25,26 The urinary excretion of vitamin B12, folic acid, and the citrovorum factor by different individuals, even on controlled diets, was found to vary through rather wide ranges (2- to 9-fold) though the study was not concerned with individual differences and individual patterns were not established. 27... 

Johnson and colleagues made a provocative observation in the course of exploratory preclinical toxicological studies of vincristine, namely, that folinic acid (Leucovorin citrovorum factor 5-formyl-5,6,7,8-tetrahy-drofolic acid) was able to protect mice from the toxicity of high doses of vincristine lb). Vincristine, at a dose of 2.5 mg/kg administered intravenously, resulted in a mortality of 90% over a period of 30 days, but treatment with folinic acid lowered the mortality to 25%. The protection against vincristine toxicity did not occur when folic acid was substituted for folinic acid. A report has appeared (45) indicating that there is no specific protective effect of folinic acid against vincristine toxicity in mice and that the protection can be observed by comparable treatment with isotonic saline solution. As discussed in Section Vll, there is not conclusive evidence that folinic acid is able to ameliorate vincristine toxicity in humans (46). 

Leucovorin Calcium (Folinic Acid Citrovorum Factor)... 

N5-Formyl-THF (leucovorin). The N5-formyl derivative of THF (5-formyl-THF) is a growth factor for Leuconostoc citrovorum. Following this discovery in 1949 it was called the "citrovorum factor" or leucovorin. 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

Citrovorum factor) L se antianemic, growth factor, antidote... 

Inhibition of nudeobase synthesis (2). Tet-rahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 274). The folate analogues aminopterin and methotrexate (amethopterin) inhibit enzyme activity. Cellular stores of THF are depleted. The effect of these antimetabolites can be reversed by administration of folinic acid (5-formyl-THF, leucovorin, citrovorum factor). Hydroxyurea (hydroxycarbamide) inhibits ribonucleotide reductase that normally converts ribonucleotides into deoxyribonucleotides subsequently used as DNA building blocks. 

Pitman SW, Parker LM,Tattersall MNH, Jaffe N, Frei E.CIinical trial of high-dose methotrexate with citrovorum factor-toxicologic... 

The fifth tetrahydrofolate compound is 5-formyl THF (folinicacid, citrovorum factor). This compound is not a coenzyme, but it can be converted to any of the active coenzyme forms. It is administered after treatment with the dihydrofolate reductase inhibitor, methotrexate (F ig. 8.47), as a form of rescue therapy. Because it already is in the reduced tetrahydrofolate form, it does not need dihydrofolate reductase to become an active coenzyme. 

There are several one-carbon derivatives of folate (of different redox states) that function as one-carbon carriers in different metabolic processes. In all of these reactions, the one-carbon moiety is carried in a covalent linkage to one or both of the nitrogen atoms at the 5- and 10-positions of the pteroic acid portion of tetrahydrofolate. Six known forms of carrier are shown in Figure 27-4. Folinic acid (N -formyl FH4), also called leucovorin or citrovorum factor, is chemically stable and is used clinically to prevent or reverse the toxic effect of folate antimetabolites, such as methotrexate and pyrimethamine. The formation and interconversion of some metabolites of... 

D16. Doctor, V. M., In vitro studies on the conversion of folic acid to citrovorum factor. J. Biol. Chem. 222, 959-968 (1956). 

Antifolate chemotherapy produced the first cure of a solid tumor, choriocarcinoma. Introduction of high-dose regimens with rescue of host toxicity by the reduced folate, leucovorin (folinic acid, citrovorum factor, 5-formyl tetrahydrofolate, N -formyl FH ), further extended the effectiveness of these drugs to both systemic and CNS lymphomas, osteogenic sarcoma, and leukemias. Most recently, analogs that differ from methotrexate in their transport properties and sites of action have proven useful in treating other cancers. 

C20H23N7O7, Mr 473.45, pale yellow crystals +3 H2O, mp. 248 -250 °C (decomp.), [a]n +16.8° (aqueous hydrogen carbonate). F. occurs in various microorganisms in which it acts as a growth factor e. g., for the lactic acid bacterium Leuconostoc citrovorum, therefore, it is also known as citrovorum factor. F. functions as an active 1-C unit (cf. folic acid) and formyl group transfer agent in the metabolism of folic acid tetrahy-drofolic acid. F. is accessible by synthesis and its calcium salt is used therapeutically as an antidote for folic acid antagonists such as methotrexate. 

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