Folinic acid (FA) is an ubiquitous member of biological folate pools, usually comprising 10-20% of total cellular folates. Folic acid is commonly used as a protective agent in combination with methotrexate (MTX), an anticancer compound, to mitigate the cytotoxic effects induced by MTX[1]. Folinic acid also serves as a sensitizer of 5-fluorouracil (5-FU)/FdUrd through inhibition of thymidylate synthase in tumor cells, thus potentiating the antitumor activity of 5-fluorouracil[4].
In vitro, Folinic acid (5 and 50µg/mL; 40h) reduced MTX-induced cytogenetic damage in V79 cells, as evidenced by decreased percentages of micronucleated binucleated cells (MNBN) and aberrant cells (Abs), alongside increased nuclear division index (NDI) and mitotic index (MI)[1]. Folinic acid (0.1-10μM; 72h) concentration-dependently enhances FdUrd (0.03μM) cytotoxicity in both DLD-1 and HCT116 cells[3]. Folinic acid (10μM; 24-48h) in combination with bortezomib (3-300nM) significantly enhances cytotoxicity and caspase-related apoptosis in HCT116 and HT29 cells[4].
In vivo, Folinic acid (1.5, 20, or 50mg/kg/dose; p.o.; twice daily), administered 6h after each daily TMX dose (25, 35, or 45mg/kg/d; p.o.), is able to protect rats against the toxicity induced by repeated daily TMX administration[1]. Folinic acid (7mg/kg; i.p.; every other day for 3 weeks) is able to reverse the inhibitory effect of MTX on skeletal growth in juvenile male Balb/c mice[2]. Folinic acid (80mg/kg; i.p.; twice a week for 2 weeks) in combination with bortezomib (0.5mg/kg) is able to induce apoptosis and inhibit tumor growth to a greater extent than bortezomib alone in HCT116 xenograft mouse model[4]. Topical administration of 2.5% Folinic acid facilitates cutaneous wound healing in rats, manifested by enhanced re‑epithelialization, neovascularization, collagen deposition, and progressive mast cell increase[5].
References:
[1] Keshava C, Keshava N, Whong WZ, Nath J, Ong TM. Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells. Mutat Res. 1998;397(2):221-228.
[2] Iqbal MP, et al. Effect of methotrexate and folinic acid on skeletal growth in mice. Acta Paediatr. 2003 Dec;92(12):1438-44.
[3] Tsukihara H, Tsunekuni K, Takechi T. Folic Acid-Metabolizing Enzymes Regulate the Antitumor Effect of 5-Fluoro-2'-Deoxyuridine in Colorectal Cancer Cell Lines. PLoS One. 2016;11(9):e0163961.
[4] Wang S, Wang L, Zhou Z, et al. Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells. Sci Rep. 2017;7(1):682.
[5] Duman N, Duman R, Tosun M, et al. Topical folinic acid enhances wound healing in rat model. Adv Med Sci. 2018;63(2):347-352.