The diligent try an excellent 71-year-old Caucasian boy have been diagnosed inside 1997 with prostate disease

The diligent try an excellent 71-year-old Caucasian boy have been diagnosed inside 1997 with prostate disease

His baseline PSA level was 8 ng/mL. All six biopsy cores contained 90% Gleason scores of 3+4 = 7 adenocarcinoma, and peri-neural invasion was observed. The patient’s clinical stage was T1c. He elected therapy with intermittent androgen deprivation (IAD) with flutamide, leuprolide, and finasteride. In dos007, after the third cycle of IAD, his PSA level slowly increased into the 3 ng/mL range and his serum testosterone remained < 20 ng/dl. Sequential anti-androgen withdrawal, ketoconazole, diethylstilbestrol, estramustine, and transdermal ?-estradiol, along with a trial of low-dose oral cyclophosphamide and capecitabine, all while he was being treated with leuprolide maintenance therapy, were either transiently effective or unsuccessful.

You will find interruption regarding regular intracellular methylated folate models and all or any of these perturbations go for increased frequency out of colon, breast, gastric, cervical and you may prostate malignant tumors

The patient was restaged, with a bone scan and computed tomography yielding only evidence of biochemical PSA relapse. He then received docetaxel 30 mg/m 2 for three of every four weeks while his leuprolide treatment was continued. His PSA level continued to rise exponentially for 18 weeks, thus we assumed docetaxel resistance. The patient revealed that he was ingesting a supplement of 10 daily dose units of Intrinsi Btwelve/folate (Metagenics, San Clemente, CA, USA. Each dose unit contained 20 mg of porcine intrinsic factor and 500 ?g of vitamin B12, as well as 400 ?g of FA, and 400 ?g of L-5-methyltetrahydrofolate (for a total of 800 ?g of mixed FAs). On , his PSA level reached 21.3 ng/mL, and on , his serum FA level was assayed to be 134 ng/mL (normal range 5 ng/mL to 24 ng/mL), his serum vitamin B12 level was > 1500 pg/mL (normal range 300 pg/mL to 900 pg/mL), his serum testosterone level was < 20 ng/mL (normal range 212 ng/mL to 755 ng/mL), and his total serum homocysteine was 12.0 ?mol/L (normal range 7 ?mol/L to 12 ?mol/L).

The patient discontinued the oral supplement on day 900 (Figure 1), and within two weeks his serum PSA level started to decline. At the time of this writing, his PSA level is 2.08 ng/mL. He continues to receive weekly docetaxel chemotherapy. His last serum FA level was 4.0 ng/mL (borderline deficient), his serum vitamin B12 level was 377 pg/mL, and his total serum homocysteine level was 17.8 ?mol/L.


High-dose folate, FA, and vitamin B12 metabolic interactions may have modulated this patient’s response to PSA treatment. Figure 2 sumin biochemistry as they relate to the de novo and salvage pathways of DNA-thymine (DNA-T) and epigenetic regulatory effects of CH3 group transfer to the universal methylator S-adenosylmethionine (SAM) by FA and its vitamers.

Metabolic interactions between folates and vitamins B 12 , B 6 , and B 2 . 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. 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.

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