Editing Folate (section)

===Cancer===
Chronically insufficient intake of folate may increase the risk of colorectal, breast, ovarian, pancreatic, brain, lung, cervical, and prostate cancers.<ref name=lpi/><ref>{{cite journal|vauthors=Jägerstad M|title=Folic acid fortification prevents neural tube defects and may also reduce cancer risks|journal=Acta Paediatrica|volume=101|issue=10|pages=1007–12|date=October 2012|pmid=22783992|doi=10.1111/j.1651-2227.2012.02781.x|s2cid=3458384|doi-access=free}}</ref><ref name="cebp.aacrjournals">{{cite journal|vauthors=Weinstein SJ, Hartman TJ, Stolzenberg-Solomon R, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D|title=Null association between prostate cancer and serum folate, vitamin B(6), vitamin B(12), and homocysteine|journal=Cancer Epidemiology, Biomarkers & Prevention|volume=12|issue=11 Pt 1|pages=1271–2|date=November 2003|pmid=14652294|url=http://cebp.aacrjournals.org/content/12/11/1271.long|url-status=live|archive-url=https://web.archive.org/web/20170222201134/http://cebp.aacrjournals.org/content/12/11/1271.long|archive-date=22 February 2017}}</ref>

Early after fortification programs were implemented, high intakes were theorized to accelerate the growth of preneoplastic lesions that could lead to cancer, specifically colon cancer.<ref name=Chustecka2009>{{cite web|url=http://www.medscape.com/viewarticle/591111|vauthors=Chustecka Z|title=Folic-acid fortification of flour and increased rates of colon cancer|year=2009|website=Medscape|access-date=9 November 2009|archive-date=25 November 2010|archive-url=https://web.archive.org/web/20101125195847/http://www.medscape.com/viewarticle/591111|url-status=live}}</ref><ref name=Mason2007/> Subsequent meta-analyses of the effects of low versus high dietary folate, elevated serum folate, and supplemental folate in the form of folic acid have reported at times conflicting results. Comparing low to high dietary folate showed a modest but [[statistical significance|statistically significant]] reduced risk of colon cancer.<ref>{{cite journal |vauthors=Kim DH, Smith-Warner SA, Spiegelman D, Yaun SS, Colditz GA, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Harnack L, Jacobs EJ, Leitzmann M, Mannisto S, Miller AB, Potter JD, Rohan TE, Schatzkin A, Speizer FE, Stevens VL, Stolzenberg-Solomon R, Terry P, Toniolo P, Weijenberg MP, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter DJ |title=Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer |journal=Cancer Causes Control |volume=21 |issue=11 |pages=1919–30 |date=November 2010 |pmid=20820900 |pmc=3082430 |doi=10.1007/s10552-010-9620-8}}</ref> For prostate cancer risk, comparing low to high dietary folate showed no effect.<ref name=Wang2014>{{cite journal|vauthors=Wang R, Zheng Y, Huang JY, Zhang AQ, Zhou YH, Wang JN|title=Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies|journal=BMC Public Health|volume=14|issue=1|page=1326|date=December 2014|pmid=25543518|pmc=4320532|doi=10.1186/1471-2458-14-1326 |doi-access=free }}</ref><ref name=Tio2014>{{cite journal |vauthors=Tio M, Andrici J, Cox MR, Eslick GD |s2cid=27184844 |title=Folate intake and the risk of prostate cancer: a systematic review and meta-analysis |journal=Prostate Cancer Prostatic Dis. |volume=17 |issue=3 |pages=213–9 |date=September 2014 |pmid=24819234 |doi=10.1038/pcan.2014.16 |doi-access=free }}</ref> A review of trials that involved folic acid dietary supplements reported a statistically significant 24% increase in prostate cancer risk.<ref name=Wien2012>{{cite journal|vauthors=Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M|title=Cancer risk with folic acid supplements: a systematic review and meta-analysis|journal=BMJ Open|volume=2|issue=1|pages=e000653|date=January 2012|pmid=22240654|pmc=3278486|doi=10.1136/bmjopen-2011-000653}}</ref> It was shown that supplementation with folic acid at 1,000 to 2,500&nbsp;μg/day – the amounts used in many of the cited supplement trials<ref name=Wien2012/><ref name="Qin2013">{{cite journal |vauthors=Qin X, Cui Y, Shen L, Sun N, Zhang Y, Li J, Xu X, Wang B, Xu X, Huo Y, Wang X |date=September 2013 |title=Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials |journal=Int. J. Cancer |volume=133 |issue=5 |pages=1033–41 |doi=10.1002/ijc.28038 |pmid=23338728 |s2cid=19830376|doi-access=free }}</ref> – would result in higher concentrations of serum folate than what is achieved from diets high in food-derived folate. The second supplementation review reported no significant increase or decrease in total cancer incidence, colorectal cancer, other gastrointestinal cancer, genitourinary cancer, lung cancer or hematological malignancies in people who were consuming folic acid supplements.<ref name=Qin2013/> A third supplementation meta-analysis limited to reporting only on colorectal cancer incidence showed that folic acid treatment was not associated with colorectal cancer risk.<ref>{{cite journal |vauthors=Qin T, Du M, Du H, Shu Y, Wang M, Zhu L |title=Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials |journal=Sci Rep |volume=5 |page=12044 |date=July 2015 |pmid=26131763 |pmc=4487230 |doi=10.1038/srep12044 |bibcode=2015NatSR...512044Q }}</ref>

====Anti-folate chemotherapy====
Folate is important for cells and tissues that divide rapidly.<ref name="Oldref_2">{{cite journal | vauthors = Kamen B | title = Folate and antifolate pharmacology | journal = Seminars in Oncology | volume = 24 | issue = 5 Suppl 18 | pages = S18-30-S18-39 | date = October 1997 | pmid = 9420019 }}</ref> Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate drug [[methotrexate]] is often used to treat cancer because it inhibits the production of the active tetrahydrofolate (THF) from the inactive dihydrofolate (DHF).<ref name="Gonen_2012">{{cite journal | vauthors = Gonen N, Assaraf YG | title = Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance | journal = Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy | volume = 15 | issue = 4 | pages = 183–210 | date = August 2012 | pmid = 22921318 | doi = 10.1016/j.drup.2012.07.002 }}</ref> However, methotrexate can be toxic,<ref>{{cite journal | vauthors = Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS | title = Effect of glutamine on methotrexate efficacy and toxicity | journal = Annals of Surgery | volume = 227 | issue = 5 | pages = 772–8; discussion 778–80 | date = May 1998 | pmid = 9605669 | pmc = 1191365 | doi = 10.1097/00000658-199805000-00018 }}</ref><ref>{{cite journal | vauthors = Wolff JE, Hauch H, Kühl J, Egeler RM, Jürgens H | title = Dexamethasone increases hepatotoxicity of MTX in children with brain tumors | journal = Anticancer Research | volume = 18 | issue = 4B | pages = 2895–9 | year = 1998 | pmid = 9713483 }}</ref><ref>{{cite journal | vauthors = Kepka L, De Lassence A, Ribrag V, Gachot B, Blot F, Theodore C, Bonnay M, Korenbaum C, Nitenberg G | title = Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure | journal = Leukemia & Lymphoma | volume = 29 | issue = 1–2 | pages = 205–9 | date = March 1998 | pmid = 9638991 | doi = 10.3109/10428199809058397 }}</ref> producing side effects such as inflammation in the digestive tract that make eating normally more difficult. Bone marrow depression (inducing leukopenia and thrombocytopenia) and acute kidney and liver failure have been reported.

[[Folinic acid]], under the drug name [[leucovorin]], a form of folate (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate.<ref>{{cite journal | vauthors = Branda RF, Nigels E, Lafayette AR, Hacker M | title = Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats | journal = Blood | volume = 92 | issue = 7 | pages = 2471–6 | date = October 1998 | pmid = 9746787 | doi = 10.1182/blood.V92.7.2471 | doi-access = free }}</ref> Folic acid supplements have little established role in cancer chemotherapy.<ref>{{cite journal | vauthors = Shiroky JB | title = The use of folates concomitantly with low-dose pulse methotrexate | journal = Rheumatic Disease Clinics of North America | volume = 23 | issue = 4 | pages = 969–80 | date = November 1997 | pmid = 9361164 | doi = 10.1016/S0889-857X(05)70369-0 }}</ref><ref>{{cite journal | vauthors = Keshava C, Keshava N, Whong WZ, Nath J, Ong TM | title = Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells | journal = Mutation Research | volume = 397 | issue = 2 | pages = 221–8 | date = February 1998 | pmid = 9541646 | doi = 10.1016/S0027-5107(97)00216-9 | bibcode = 1998MRFMM.397..221K }}</ref> The supplement of folinic acid in people undergoing methotrexate treatment is to give less rapidly dividing cells enough folate to maintain normal cell functions. The amount of folate given is quickly depleted by rapidly dividing (cancer) cells, so this does not negate the effects of methotrexate.