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

Abstract

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.

Pharmacologic modulation of 5-fluorouracil by folinic acid and pyridoxine for treatment of patients with advanced breast carcinoma

“…The remarkable antitumor activity observed in the present pilot study may represent the difference with that reported elsewhere in trials using combination regimens administered in their standard form. Strength of antitumor activity achieved in the present study is of similar level than that recently reported in patients with advanced carcinomas of the digestive tract treated with regimens including FUra, FA, and PN 52 . Murine experiments reported herein indicate that parenteral PM carries an advantage over PN to expand intracellular PLP pools which may facilitate SHMT-dependent synthesis of CH 2 -H 4 PteGlu to improve the modulation of FUra.…”

“…Modulation of FUra by high-dose FA and PN in tandem was used in a pilot study for treatment of patients with unresectable or metastatic colorectal adenocarcinoma, pancreas adenocarcinoma, and squamous cell carcinoma of the esophagus 52 . Addition of high-dose PN to standard treatment regimens comprising FUra and FA led to high rate of antitumor responses of early onset and great magnitude with no detrimental effect on toxicity from that expected using these regimens in absence of PN.…”

Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line

“…Additionally, both clinical trials and in vivo animal studies have demonstrated that methyl-donor micronutrient intake can reduce the risk of development of several cancer types by altering DNA methylation status [ 7 , 9 ]. Moreover, a pilot study reported that a high dose of vitamin B6 may enhance the antitumor activity of standard chemotherapies in the case of colorectal, pancreatic, and esophageal carcinomas [ 20 ].…”

Treatment of patients with carcinomas in advanced stages with 5-fluorouracil, folinic acid and pyridoxine in tandem

“…Based on these experimental findings we conducted a pilot clinical study for treatment of patients with digestive tract, and breast carcinomas in advanced stages with poor prognostic features who were not amenable to resection, radiotherapy, nor to any chemotherapy with curative intent, and whose standard chemotherapy regimens included a combination of FUra and FA, consisting in addition of high dose pyridoxine to these regimens. Early results were previously reported 37 , 38 . We present herein now the final update that included fifty patients entered from June 2014 to March 2023.…”