Dihydrofolate Reductase Gene Variations in Susceptibility to Disease and Treatment Outcomes

Abstract

Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). THF is needed for the action of folate-dependent enzymes and is thus essential for DNA synthesis and methylation. The importance of this reaction is demonstrated by the effectiveness of antifolate medications used to treat cancer by inhibiting DHFR, thereby depleting THF and slowing DNA synthesis and cell proliferation. Due to the pivotal role that DHFR plays in folate metabolism and cancer treatment, changes in the level of DHFR expression can affect susceptibility to a variety of diseases dependent on folate status such as spina bifida and cancer. Likewise, variability in DHFR expression can affect sensitivity to anti-cancer drugs such as the folate antagonist methotrexate. Alterations in DHFR expression can be due to polymorphisms in the DHFR gene. Several variations have recently been described in DHFR, including promoter polymorphisms, the 19-bp deletion allele and variations in 3’UTR. These polymorphisms seem to be functional, affecting mRNA levels through various interesting mechanisms, including regulation through RNA interference. Several groups have assessed the association of these polymorphisms with folate levels, risk of cancer and spina bifida as well as the outcome of diseases treated with MTX. The latter may lead to different treatment schedules, improving treatment efficacy and/or allowing for a reduction in drug side effects. This review will summarize present knowledge regarding the predictive potential of DHFR polymorphisms in disease and treatment.

Functional Inclusion Bodies Produced in Bacteria as Naturally Occurring Nanopills for Advanced Cell Therapies

“…[ 36 ] Defi ciencies or alterations of DHFR have been linked to megaloblastic anemia, [ 37 ] inherited spina bifi da and related neurological disorders and cancer. [ 38 ] DHFR activity is located at the cytosol. [ 39 ] CAT (homotetramer, 59.7 kDa per monomer) effi ciently catalyzes the decomposition of hydrogen peroxide to water and oxygen and it acts, in red blood cells, as a sink for hydrogen peroxide and superoxide removal.…”

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

“…The application of these quinazoline analogues was also recommended for combined inhibition of epidermal growth factor receptor and hDHFR. Besides its use in cancer therapy, hDHFR is also known as an important target for the treatment of rheumatoid arthritis [1,188]. Potential inhibitors of hDHFR (109-111) ( Fig.…”

“…Infections caused by multidrug-resistant (MDR) bacteria are significant global healthcare problem. Thus, understanding the mechanisms of drug resistance is one of the most important trends underway research both in the treatment of infectious diseases, as well as work on treatment methods of cancer [1,2]. The molecular target connecting these equally important directions of research is dihydrofolate reductase (DHFR), an enzyme that catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of dihydrofolate to tetrahydrofolate (7,6,7, in microbial and eukaryotes cells [3].…”

Analysis of the mRNA Expression of Chemotherapy-Related Genes in Colorectal Carcinoma Using the Danenberg Tumor Profile Method

“…THF is required for the activity of folate-dependent enzymes and is thus essential for DNA synthesis and methylation. DHFR is a target of the folate antagonist methotrexate, and DHFR expression can affect chemosensitivity [11]. ERCC-1 is a biomarker that can be used to predict survival in colorectal cancer patients receiving combination oxaliplatin and fluorouracil [12].…”