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Journal of Oncology
Volume 2010 (2010), Article ID 934359, 5 pages
Review Article

CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

1Clinical Medicine, The GI Oncology Section of the Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, Milstein Hospital, 177 Fort Washington Avenue, Suite 6-435, NY 10032, USA
2Oncology Unit, Third Department of Medicine, Sotiria General Hospital, Athens Medical School, Mesogion 152, Athens 11527, Greece

Received 12 September 2010; Revised 2 November 2010; Accepted 8 November 2010

Academic Editor: Dominic Fan

Copyright © 2010 Muhammad Wasif Saif et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Intracellular reduced folate exists as a “pool” of more than 6 interconvertable forms. One of these forms, 5,10 methylenetetrahydrofolic acid (CH2THF), is the key one-carbon donor and reduced folate substrate for thymidylate synthase (TS). This pathway has been an important target for chemotherapy as it provides one of the necessary nucleotide substrates for DNA synthesis. The fluoropyrimidine 5-fluorouracil (5-FU) exerts its main cytotoxic activity through TS inhibition. Leucovorin (5-formyltetrahydrofolate; LV) has been used to increase the intracellular reduced folate pools and enhance TS inhibition. However, it must be metabolized within the cell through multiple intracellular enzymatic steps to form CH2THF. CoFactor (USAN fotrexorin calcium, (dl)-5,10,-methylenepteroyl-monoglutamate calcium salt) is a reduced folate that potentiates 5-FU cytotoxicity. According to early clinical trials, when 5-FU is modulated by CoFactor instead of LV, there is greater anti-tumor activity and less toxicity. This review presents the emerging role of CoFactor in colorectal and nongastrointestinal malignancies.