Control of prostate cancer associated with withdrawal of a supplement containing folic acid, L-methyltetrahydrofolate and vitamin B12: a case report

Abstract

Introduction: This is the first report of possible direct stimulation of hormone-resistant prostate cancer or interference of docetaxel cytotoxicity of prostate cancer in a patient with biochemical relapse of prostatic-specific antigen. This observation is of clinical and metabolic importance, especially at a time when more than 80 countries have fortified food supplies with folic acid and some contemplate further fortification with vitamin B12.

Case presentation: Our patient is a 71-year-old Caucasian man who had been diagnosed in 1997 with prostate cancer, stage T1c, and Gleason score 3+4 = 7. His primary treatment included intermittent androgen deprivation therapy including leuprolide + bicalutamide + deutasteride, ketoconazole + hydrocortisone, nilandrone and flutamide to resistance defined as biochemical relapse of PSA. While undergoing docetaxel therapy to treat a continually increasing prostate-specific antigen level, withdrawal of 10 daily doses of a supplement containing 500 μg of vitamin B12 as cyanocobalamin, as well as 400 μg of folic acid as pteroylglutamic acid and 400 μg of L-5-methyltetrahydrofolate for a combined total of 800 μg of mixed folates, was associated with a return to a normal serum prostatic-specific antigen level.

Conclusion: This case report illustrates the importance of the effects of supplements containing large amounts of folic acid, L-5-methyltetrahydrofolate, and cyanocobalamin on the metabolism of prostate cancer cells directly and/or B vitamin interference with docetaxel efficacy. Physicians caring for patients with prostate cancer undergoing watchful waiting, hormone therapy, and/or chemotherapy should consider the possible acceleration of tumor growth and/or metastasis and the development of drug resistance associated with supplement ingestion. We describe several pathways of metabolic and epigenetic interactions that could affect the observed changes in serum levels of prostate-specific antigen.

Figure 1

The clinical course of our patient's prostatic-specific antigen response.

Figure 2

Metabolic interactions between folates and vitamins B₁₂, B₆, and B₂. 677C → T thermolabile polymorphism with weakened interaction with B2 NAD cofactor disables MTHFR function by up to 70% in homozygotes. 15% of population is homozygous (2 inherited genes) 50% is heterozygous (one inherited gene). In the presence of this mutation (677C → T) when folate is plentiful this pathway provides adequate SAM for DNA methylation maintenance and shunts more 5,10 methylene THF to support DNA synthesis with less Uracil misincorporation into DNA with less 50% decreased incidence of colon cancer and acute lymphocytic leukaemia. However, in the presence of the mutation, if folate is low, then SAM DNA methylation may increase OR decrease and de novo DNA thymidine synthesis may decrease. There is disruption of normal intracellular methylated folate forms and all or some of these perturbations favour increased incidence of colon, breast, gastric, cervical and prostate cancer. Under most circumstances DNA synthesis through dTMP generation takes precedence over SAM DNA methlyation. Serine Hydroxymethyltransferase (SHMT) recently found to shift folate metabolism in the direction favoring de novo dTMP - DNA synthesis. B2 found to modulate (lessen) effects of MTHFR polymorphisms. Diet and all B vitamin levels modulate various folate pathways and therefore risks for malignancy!. Newly noted polymorphisms of DHFR (rs1677693 & rs1643659) have 30% decreased risk while MTR polymorphism (rs4659744) has 25% decreased risk of colon cancer only in the absence of FA supplements or FA supplemented diet. Changes in B vitamin concentrations and enzyme polymorphisms may produce unpredictable DNA methylation changes in part by varying DNA methyl transferase concentrations and SAM/SAH concentrations i.e. folate depletion may cause global DNA hypomethylation and specific CpG hypermethylations.