{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:25:23Z","timestamp":1768458323432,"version":"3.49.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Supplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5\u2032-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of FUra in a synergistic interaction mode. We report a pilot study in 13 patients with previously untreated advanced carcinoma of the digestive tract to assess the impact of high-dose pyridoxine (PN) on the antitumor activity of regimens comprising FUra and FA. Five patients had colorectal adenocarcinoma (CRC); 5 had pancreas adenocarcinoma (PC); and 3 had squamous cell carcinoma of the esophagus (EC). Patients with CRC and with PC received oxaliplatin, irinotecan, FUra and FA, and patients with EC had paclitaxel, carboplatin, FUra and FA. PN iv from 1000 to 3000\u00a0mg\/day preceded each administration of FA and FUra. Eleven patients responded. Two patients with CRC attained CRs and 3 had PRs with reduction rates\u2009\u2265\u200978%. Two patients with PC attained CRs, and 2 had PRs with reduction rates\u2009\u2265\u200979%. Responders experienced disappearance of most metastases. Of 3 patients with EC, 2 attained CRs. Median time to attain a response was 3\u00a0months. Unexpected toxicity did not occur. Results suggest that high-dose vitamin B6 enhances antitumor potency of regimens comprising FUra and FA.<\/jats:p>","DOI":"10.1038\/s41598-021-92110-5","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T10:03:04Z","timestamp":1623837784000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Pharmacologic modulation of 5-fluorouracil by folinic acid and high-dose pyridoxine for treatment of patients with digestive tract carcinomas"],"prefix":"10.1038","volume":"11","author":[{"given":"David","family":"Machover","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wathek","family":"Almohamad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Castagn\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"Desterke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e9a","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yann","family":"Gaston-Math\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claude","family":"Boucheix","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Goldschmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"92110_CR1","first-page":"1803","volume":"66","author":"D Machover","year":"1982","unstructured":"Machover, D. et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: A pilot study. Cancer Treat Rep. 66, 1803\u20131807 (1982).","journal-title":"Cancer Treat Rep."},{"key":"92110_CR2","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1200\/JCO.1992.10.6.896","volume":"10","author":"P Piedbois","year":"1992","unstructured":"Piedbois, P. et al. For the Advanced Colorectal Cancer Meta-Analysis Project. Modulation of 5-fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J. Clin. Oncol. 10, 896\u2013903 (1992).","journal-title":"J. Clin. Oncol."},{"key":"92110_CR3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/978-1-4684-1378-6_9","volume-title":"Single Agents in Cancer Chemotherapy","author":"RB Livingstone","year":"1970","unstructured":"Livingstone, R. B. & Carter, S. K. 5-Fluorouracil. In Single Agents in Cancer Chemotherapy (eds Livingston, R. B. & Carter, S. K.) 195\u2013226 (IFI\/Plenum, 1970)."},{"key":"92110_CR4","first-page":"3940","volume":"50","author":"JA Houghton","year":"1990","unstructured":"Houghton, J. A. et al. Influence of dose of [6RS] leucovorin on reduced folate pools and 5-fluorouracil-mediated thymidylate synthase inhibition in human colon adenocarcinoma xenografts. Cancer Res. 50, 3940\u20133946 (1990).","journal-title":"Cancer Res."},{"key":"92110_CR5","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1007\/BF00685660","volume":"34","author":"D Voeller","year":"1994","unstructured":"Voeller, D. & Allegra, C. J. Intracellular metabolism of 5-methyltetrahydrofolate and 5-formyltetrahydrofolate in a human breast-cancer cell line. Cancer Chemother. Pharmacol. 34, 491\u2013496 (1994).","journal-title":"Cancer Chemother. Pharmacol."},{"key":"92110_CR6","first-page":"2592","volume":"49","author":"JE Wright","year":"1989","unstructured":"Wright, J. E. et al. Selective expansion of 5,10-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo. Cancer Res. 49, 2592\u20132596 (1989).","journal-title":"Cancer Res."},{"key":"92110_CR7","first-page":"789","volume":"51","author":"A Romanini","year":"1991","unstructured":"Romanini, A. et al. Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin. Cancer Res. 51, 789\u2013793 (1991).","journal-title":"Cancer Res."},{"key":"92110_CR8","first-page":"3476","volume":"51","author":"Z-G Zhang","year":"1991","unstructured":"Zhang, Z.-G. & Rustum, Y. M. Effects of diastereoisomers of 5-formyltetrahydrofolate on cellular growth, sensitivity to 5-fluoro-2\u2032-deoxyuridine, and methylenetetrahydrofolate polyglutamate levels in HCT-8 cells. Cancer Res. 51, 3476\u20133481 (1991).","journal-title":"Cancer Res."},{"key":"92110_CR9","first-page":"36","volume":"52","author":"DM Boarman","year":"1992","unstructured":"Boarman, D. M. & Allegra, C. J. Intracellular metabolism of 5-formyl tetrahydrofolate in human breast and colon cell lines. Cancer Res. 52, 36\u201344 (1992).","journal-title":"Cancer Res."},{"key":"92110_CR10","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/S0006-2952(01)00560-3","volume":"61","author":"D Machover","year":"2001","unstructured":"Machover, D. et al. Cytotoxic synergism of methioninase in combination with 5-fluorouracil and folinic acid. Biochem. Pharmacol. 61, 867\u2013876 (2001).","journal-title":"Biochem. Pharmacol."},{"key":"92110_CR11","first-page":"3493","volume":"50","author":"JA Houghton","year":"1990","unstructured":"Houghton, J. A. et al. Relationship between dose rate of [6RS]leucovorin administration, plasma concentrations of reduced folates, and pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts. Cancer Res. 50, 3493\u20133502 (1990).","journal-title":"Cancer Res."},{"key":"92110_CR12","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1021\/bi00700a012","volume":"13","author":"DV Santi","year":"1974","unstructured":"Santi, D. V., McHenry, C. S. & Sommer, H. Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13, 471\u2013481 (1974).","journal-title":"Biochemistry"},{"key":"92110_CR13","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1073\/pnas.75.2.980","volume":"75","author":"B Ullman","year":"1978","unstructured":"Ullman, B., Lee, M., Martin, D. W. Jr. & Santi, D. V. Cytotoxicity of 5-fluoro-2\u2032-deoxyuridine: Requirement for reduced folate cofactors and antagonism by methotrexate. Proc. Natl. Acad. Sci. USA 75, 980\u2013983 (1978).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"92110_CR14","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1021\/bi00612a022","volume":"17","author":"PV Danenberg","year":"1978","unstructured":"Danenberg, P. V. & Danenberg, K. D. Effect of 5,10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2\u2032-deoxyuridylate from thymidylate synthetase: Evidence for an ordered mechanism. Biochemistry 17, 4018\u20134024 (1978).","journal-title":"Biochemistry"},{"key":"92110_CR15","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0006-2952(81)90085-X","volume":"30","author":"A Lockshin","year":"1981","unstructured":"Lockshin, A. & Danenberg, P. V. Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetase. Biochem. Pharmacol. 30, 247\u2013257 (1981).","journal-title":"Biochem. Pharmacol."},{"key":"92110_CR16","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1007\/s00018-008-8557-5","volume":"66","author":"MD Wyatt","year":"2009","unstructured":"Wyatt, M. D. & Wilson, D. M. III. Participation of DNA repair in the response to 5-fluorouracil. Cell Mol. Life Sci. 66, 788\u2013799 (2009).","journal-title":"Cell Mol. Life Sci."},{"key":"92110_CR17","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1016\/j.neo.2018.10.006","volume":"20","author":"C Mani","year":"2018","unstructured":"Mani, C., Pai, S., Papke, C. M., Palle, K. & Gmeiner, W. H. Thymineless death by the fluoropyrimidine polymer F10 involves replication fork collapse and is enhanced by Chk1 inhibition. Neoplasia 20, 1236\u20131245 (2018).","journal-title":"Neoplasia"},{"key":"92110_CR18","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.dnarep.2015.04.026","volume":"32","author":"D Cortez","year":"2015","unstructured":"Cortez, D. Preventing replication fork collapse to maintain genome integrity. DNA Repair 32, 49\u2013157 (2015).","journal-title":"DNA Repair"},{"key":"92110_CR19","doi-asserted-by":"publisher","first-page":"23713","DOI":"10.18632\/oncotarget.15785","volume":"8","author":"A Hagenkort","year":"2017","unstructured":"Hagenkort, A. et al. dUTPase inhibition augments replication defects of 5-fluorouracil. Oncotarget 8, 23713\u201323726 (2017).","journal-title":"Oncotarget"},{"key":"92110_CR20","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/0005-2744(78)90128-6","volume":"526","author":"CW Jones III","year":"1978","unstructured":"Jones, C. W. III. & Priest, D. G. Interaction of pyridoxal 5\u2032-phosphate with aposerine hydroxymethyltransferase. Biochim. Biophys. Acta. 526, 369\u2013374 (1978).","journal-title":"Biochim. Biophys. Acta."},{"key":"92110_CR21","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.abb.2007.04.005","volume":"462","author":"C Perry","year":"2007","unstructured":"Perry, C., Yu, S., Chen, J., Matharu, K. S. & Stover, P. J. Effect of vitamin B6 availability on serine hydroxymethyltransferase in MCF-7 cells. Arch. Biochem. Biophys. 462, 21\u201327 (2007).","journal-title":"Arch. Biochem. Biophys."},{"key":"92110_CR22","doi-asserted-by":"publisher","first-page":"6456","DOI":"10.1016\/S0021-9258(19)43467-4","volume":"248","author":"LV Schirch","year":"1973","unstructured":"Schirch, L. V., Edmiston, M. & Chen, M. S. Serine transhydroxymethylase: Subunit structure and the involvement of sulfhydryl groups in the activity of the enzyme. J. Biol. Chem. 248, 6456\u20136461 (1973).","journal-title":"J. Biol. Chem."},{"key":"92110_CR23","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1111\/febs.13211","volume":"282","author":"G Giardina","year":"2015","unstructured":"Giardina, G. et al. How pyridoxal 5\u2032-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state. FEBS J. 282, 1225\u20131241 (2015).","journal-title":"FEBS J."},{"key":"92110_CR24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0009-8981(94)90226-7","volume":"229","author":"J Zempleni","year":"1994","unstructured":"Zempleni, J. & K\u00fcbler, W. The utilization of intravenously infused pyridoxine in humans. Clin. Chim. Acta 229, 27\u201336 (1994).","journal-title":"Clin. Chim. Acta"},{"key":"92110_CR25","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1146\/annurev-nutr-071714-034330","volume":"35","author":"PM Ueland","year":"2015","unstructured":"Ueland, P. M., Ulvik, A., Rios-\u00c1vila, L., Midttun, \u00d8. & Gregory, J. F. Direct and functional biomarkers of vitamin B6 status. Annu. Rev. Nutr. 35, 33\u201370 (2015).","journal-title":"Annu. Rev. Nutr."},{"key":"92110_CR26","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1093\/jn\/130.5.1115","volume":"130","author":"M Mart\u00ednez","year":"2000","unstructured":"Mart\u00ednez, M., Cuskelly, G. J., Williamson, J., Toth, J. P. & Gregory, J. F. I. I. I. Vitamin B-6 deficiency in rats reduces hepatic serine hydroxymethyl transferase and cystathionine \u03b2-synthase activities and rates of in vivo protein turnover, homocysteine remethylation and transsulfuration. J. Nutr. 130, 1115\u20131123 (2000).","journal-title":"J. Nutr."},{"key":"92110_CR27","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1124\/jpet.118.249367","volume":"366","author":"D Machover","year":"2018","unstructured":"Machover, D. et al. Enhancement of 5-fluorouracil cytotoxicity by pyridoxal 5\u2032-phosphate and folinic acid in tandem. J. Pharmacol. Exp. Ther. 366, 238\u2013243 (2018).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"92110_CR28","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1056\/NEJM198308253090801","volume":"309","author":"H Schaumburg","year":"1983","unstructured":"Schaumburg, H. et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N. Engl. J. Med. 309, 445\u2013448 (1983).","journal-title":"N. Engl. J. Med."},{"key":"92110_CR29","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1176\/ajp.135.4.472","volume":"135","author":"B Rimland","year":"1978","unstructured":"Rimland, B., Callaway, E. & Dreyfus, P. The effect of high doses of vitamin B6 on autistic children: A double blind crossover study. Am. J. Psychiatry 135, 472\u2013475 (1978).","journal-title":"Am. J. Psychiatry"},{"key":"92110_CR30","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","volume":"364","author":"T Conroy","year":"2011","unstructured":"Conroy, T. et al. For the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817\u20131825 (2011).","journal-title":"N. Engl. J. Med."},{"key":"92110_CR31","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1093\/jnci\/84.5.321","volume":"84","author":"D Machover","year":"1982","unstructured":"Machover, D. et al. Fluorouracil combined with the pure (6S)-stereoisomer of folinic acid in high doses for treatment of patients with advanced colorectal carcinoma: A phase I\u2013II study. J. Natl. Cancer Inst. 84, 321\u2013327 (1982).","journal-title":"J. Natl. Cancer Inst."},{"key":"92110_CR32","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1097\/00130404-200307000-00007","volume":"9","author":"AA Meluch","year":"2003","unstructured":"Meluch, A. A. et al. Preoperative therapy with concurrent paclitaxel\/carboplatin\/infusional 5-FU and radiation therapy in locoregional esophageal cancer: Final results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J. 9, 251\u2013260 (2003).","journal-title":"Cancer J."},{"key":"92110_CR33","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1200\/JCO.1995.13.7.1656","volume":"13","author":"M Schneider","year":"1995","unstructured":"Schneider, M. et al. Phase II trial of cisplatin, fluorouracil, and pure folinic acid for locally advanced head and neck cancer: A pharmacokinetic and clinical survey. J. Clin. Oncol. 13, 1656\u20131662 (1995).","journal-title":"J. Clin. Oncol."},{"key":"92110_CR34","first-page":"219","volume":"50","author":"EJ Freireich","year":"1966","unstructured":"Freireich, E. J., Gehan, E. A., Rall, D. P., Schmidt, L. H. & Skipper, H. E. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother. Rep. 50, 219\u2013244 (1966).","journal-title":"Cancer Chemother. Rep."},{"key":"92110_CR35","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1093\/oxfordjournals.annonc.a010489","volume":"7","author":"D Machover","year":"1996","unstructured":"Machover, D. et al. Two consecutive phase II studies of oxaliplatin (l-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann. Oncol. 7, 95\u201398 (1996).","journal-title":"Ann. Oncol."},{"key":"92110_CR36","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ejca.2018.09.006","volume":"104","author":"JB Bachet","year":"2018","unstructured":"Bachet, J. B. et al. For FFCD investigators. FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases: Results of the FFCD 1102 phase II trial. Eur. J. Cancer. 104, 108\u2013116 (2018).","journal-title":"Eur. J. Cancer."},{"key":"92110_CR37","doi-asserted-by":"publisher","first-page":"4289","DOI":"10.1245\/s10434-013-3217-x","volume":"20","author":"M Ychou","year":"2013","unstructured":"Ychou, M. et al. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial. Ann. Surg. Oncol. 20, 4289\u20134297 (2013).","journal-title":"Ann. Surg. Oncol."},{"key":"92110_CR38","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s00432-017-2534-z","volume":"144","author":"J Ta\u00efeb","year":"2018","unstructured":"Ta\u00efeb, J. et al. Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials. J. Cancer Res. Clin. Oncol. 144, 321\u2013335 (2018).","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"92110_CR39","doi-asserted-by":"publisher","first-page":"1927","DOI":"10.1016\/j.ejca.2015.06.116","volume":"51","author":"V Heinemann","year":"2015","unstructured":"Heinemann, V. et al. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur. J. Cancer 51, 1927\u20131936 (2015).","journal-title":"Eur. J. Cancer"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92110-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92110-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92110-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T09:46:52Z","timestamp":1670060812000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92110-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,16]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["92110"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-92110-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,16]]},"assertion":[{"value":"7 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.M. is the author of the International Patent entitled <i>Methods and Pharmaceutical Compositions for Treating Cancer<\/i>, published December 5, 2019 under number WO 2019\/229115 A1. Assignees: Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM); Assistance Publique-H\u00f4pitaux de Paris (APHP), and University Paris-Saclay. All other authors have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12668"}}