Pharmacologic modulation of 5-fluorouracil by folinic acid and high-dose pyridoxine for treatment of patients with digestive tract carcinomas

David Machover,Claude Boucheix,Christophe Desterke,Emma Goldschmidt,Léa Gomez,Vincent Castagné,Yann Gaston-Mathé,Wathek Almohamad

doi:10.1038/s41598-021-92110-5

David Machover, Claude Boucheix + Show 6 more

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Supplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5′-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 mg/day preceded each administration of FA and FUra. Eleven patients responded. Two patients with CRC attained CRs and 3 had PRs with reduction rates ≥ 78%. Two patients with PC attained CRs, and 2 had PRs with reduction rates ≥ 79%. Responders experienced disappearance of most metastases. Of 3 patients with EC, 2 attained CRs. Median time to attain a response was 3 months. Unexpected toxicity did not occur. Results suggest that high-dose vitamin B6 enhances antitumor potency of regimens comprising FUra and FA.

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Supplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5′-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of FUra in a synergistic interaction mode
One explanation is that supplementation of cancer cells with reduced folates in any form or quantity results in small expansion of 5–10 methylene tetrahydropteroylglutamate ( CH2-H4PteGlu) pools[4,5,6,7,8,9,10,11] up to concentrations far below that required to increase the tightness of binding of fluorodeoxyuridine monophosphate (FdUMP), the active metabolite of FUra, to thymidylate synthase (TS) for maximum stability of the ternary complex [FdUMP-TS-CH2-H4PteGlun] resulting in durable inhibition of the TS12–15 (Fig. 1)
We report a translational pilot study in previously untreated patients with advanced-stage carcinomas of the digestive tract whose standard treatment included a combination of FUra and FA, consisting in addition of pyridoxine in high dose to these regimens

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Supplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5′-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of FUra in a synergistic interaction mode. Modulation of 5-fluorouracil (FUra) by folinic acid (5-formyl tetrahydropteroylglutamate; FA)[1,2] is currently used in standard schemas for treatment of patients with colorectal, pancreas, and gastric carcinomas. This pharmacologic principle has been used to a lesser extent in patients with breast carcinoma and with head and neck squamous cell carcinoma, but not in all tumors covering the spectrum of antitumor activity of the fluoropyrimidine, which includes ovarian, prostate, and bladder c arcinomas[3]. (dUTP) and fluorodeoxyuridine triphosphate (FdUTP), which lead to genomic DNA replication defects including DNA mismatch and altered replication fork progression eliciting DNA damage cell responses and, cell death[16,17,18,19]

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