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Synergistic Combinations of Hyperthermia and Inhibitors of Nucleic Acids and Protein Synthesis
Published in Leopold J. Anghileri, Jacques Robert, Hyperthermia In Cancer Treatment, 2019
Folic acid is an essential dietary factor from which is derived a coenzyme, tetrahydrofolic acid, and a group of structurally related compounds which are concerned with metabolic transfer reactions of one-carbon units. To function as a cofactor in these reactions, folate must first be reduced to tetrahydrofolate (FH4) by dihydrofolate reductase. Inhibitors with a high affinity for this enzyme prevent the formation of FH4 and thereby cause major disruption in cellular metabolism by producing an acute intracellular deficiency of folate coenzymes.
Biologic Drug Substance and Drug Product Manufacture
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Ajit S. Narang, Mary E. Krause, Shelly Pizarro, Joon Chong Yee
The nutritional requirements of the auxotrophs form the basis of selection of cells post-transfection for those expressing exogenous proteins and has been utilized to also increase the transgene copy number and expression levels. Commonly used auxotrophs of CHO cells are the DG44 and DUKXB-11 host cell lines that are deficient in the dihydrofolate reductase (DHFR) enzyme. This enzyme reduces dihydrofolic acid to tetrahydrofolic acid, an essential cellular biochemical product for purine and thymidylate synthesis. Cells lacking the DHFR enzyme require glycine, hypoxanthine, and thymidine to grow (and are thus called triple auxotrophs). This property is utilized for the expression of a heterologous gene by co-transfection with a functional copy of the DHFR gene, such that the transfected cells do not require exogenously supplied glycine, hypoxanthine, and thymidine in the growth medium. Hence, cell culture in a deficient growth medium allows the selection of transfected cells. Another recombinant DNA expression strategy is the glutamine synthetase (GS) system utilized in GS deficient CHO cells. GS catalyzes the production of glutamine, an essential amino acid required for cellular metabolism, from glutamate and ammonia. Upon co-transfection of the recombinant gene and GS into host cells, the cells are cultivated in glutamine-free media to select for producing clones.
Recent Studies on the Neoplasia and Abnormal Cellular Differentiation in Methyl Insufficiency
Published in Maryce M. Jacobs, Vitamins and Minerals in the Prevention and Treatment of Cancer, 2018
These findings led us to reconsider other situations in which humans may be particularly sensitive to folate deficiency. Folic acid deficiency is fairly common in humans.27 Indeed, among four species investigated the hepatic levels of tetrahydrofolic acid (THFA) were lowest in humans; further, the hepatic content of dihydrofolate reductase (DHFR) was also much less in humans than in the monkey or the rat (Table 3).28 One might thus expect humans to be particularly sensitive to toxic agents which stress the folate pool. This is indeed the case with methanol, whose toxic metabolic, formic acid is detoxified by metabolism in the C1-folate pool. The relative toxicities of methanol to humans, monkeys, rats, and mice is inversely proportional to the capacity of the species to metabolize formic acid via the reduced folate pool.28 Thus, the limited experimental and clinical evidence available indicates that humans appear to be more sensitive to dietary folate deficiency than are rodents.
Pneumocystis jirovecii: a review with a focus on prevention and treatment
Published in Expert Opinion on Pharmacotherapy, 2021
R. Benson Weyant, Dima Kabbani, Karen Doucette, Cecilia Lau, Carlos Cervera
TMX-SMX is a combination of two antimicrobials that work together to inhibit the folic acid metabolic pathway. The two drugs work on different steps in the pathway, giving them synergistic activity (Figure 1). Sulfamethoxazole (SMX) is a sulfonamide that is structurally similar to para-aminobenzoic acid (PABA) and competes with PABA for the enzyme dihydropteroate synthetase (DHPS). DHPS converts PABA to dihydropteroic acid, an intermediate of tetrahydrofolic acid. Trimethoprim (TMP) is a competitive inhibitor of an enzyme further down the pathway, dihydrofolate reductase (DHFR). DHFR converts dihydrofolic acid to tetrahydrofolic acid. Tetrahydrofolic acid is essential for synthesis of purines, a component of DNA, and therefore essential for cellular reproduction. Humans can obtain and incorporate folate from food, but bacteria (and PJ) must create it endogenously.
Trimethoprim-sulfamethoxazole for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections
Published in Infectious Diseases, 2019
Aiman Bandali, Tiffany E. Bias
Trimethoprim-sulfamethoxazole is an agent with known CRE activity. Both the trimethoprim and sulfamethoxazole components work together to inhibit the production of tetrahydrofolic acid. Limited data exist for the use of trimethoprim-sulfamethoxazole for the treatment of CRE. Notably, 472 patients from the CRACKLE-1 cohort were tested for trimethoprim-sulfamethoxazole susceptibility [7,8]. Twenty-nine percent (137/472) of these isolates demonstrated susceptibility and 25 were treated with trimethoprim-sulfamethoxazole. Eleven of these patients had a urinary tract infection [7,8]. All-cause 30-day mortality was 4% [7,8]. Five patients did have a subsequent positive CRE culture, with 80% of these displaying resistance to the drug [7,8]. This agent may be useful in a certain cohort of patients.
The relationship between gene polymorphism of MTRR A66G and lower extremity deep venous thrombosis
Published in Hematology, 2018
Tetrahydrofolate in the body can be combined with a carbon unit at the 5-N and 10-N positions into tetrahydrofolic acid. Methyltetrahydrofolic acid was synthesized by MTHFR [30]. Under the catalysis of MS, homocysteine reacts with 5-methyltetrahydrofolic acid, which is demethylated into tetrahydrofolate, and homocysteine is methylated into methionine, to complete a cycle of tetrahydrofolate. Under the action of cystathionine-β-synthase (CBS), with vitamin B6 as a cofactor, homocysteine and silk amino acids combined to form cystathionine, further forming cysteine [31]. MTRR is a cofactor for MS and catalyzes the regeneration of methylcobalamin. MTRR maintains the MS in a reduced state while maintaining its methylation status by reducing vitamin B6. Studies have shown that the polymorphism of 66 A-G loci in MTRR caused methionine to be replaced by isoleucine [32]. The decrease in enzyme activity leads to hyperhomocysteinemia due to the abnormal metabolism of folic acid, which can cause vascular endothelial damage and dysfunction and stimulate the proliferation of vascular smooth muscle cell, leading to the imbalance between vascular relaxing factor and vascular contraction factor eventually, thus DVT occurs.