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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the late 1970s, researchers at the Memorial Sloan Kettering Cancer Center (US) discovered that tumor cells take in folic acid through a protein identified as Plasma Membrane Transporter (now referred to as Reduced Folate Carrier Type 1 or RFC-1), which maintains intracellular folate concentration and is encoded by the gene SLC19 A1. Further research showed that when normal cells evolve into malignant cells, they often overproduce RFC-1 to ensure they get enough folate. Thus, after a successful collaboration between researchers at the Memorial Sloane Kettering Cancer Center, SRI International, and the Southern Research Institute, pralatrexate was rationally designed in the mid-1990s to increase selective cellular transport via RFC-1. Due to the greater selectivity of pralatrexate for RFC-1, it is taken up 14 times faster than methotrexate, resulting in a higher potency. However, although pralatrexate can reduce the size of solid tumors, there is no evidence that it prolongs patient survival. The most common side effects are similar to methotrexate and include mucositis and thrombocytopenia.
Genetics and Biosynthesis of Lipopolysaccharide O-Antigens
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Wendy J. Keenleyside, Chris Whitfield
The classic O-PS assembly system is the Wzy-dependent (formerly Rfc-dependent) pathway first described in Salmonella. This involves growth of the polymer at the reducing terminus by polymerization of individual repeat units en bloc. Polymerization occurs at the periplasmic face of the plasma membrane and follows export of the newly synthesized lipid-linked O units across the plasma membrane. In contrast, the ATP-binding cassette (ABC) transporter-dependent pathway (formerly the Rfe-dependent pathway) is distinguished by growth at the nonreducing terminus through the processive polymerization of nascent O-polysaccharide at the cytoplasmic face of the plasma membrane. After polymerization, nascent O-PS is exported across the plasma membrane by a process involving an ABC transporter. It is becoming increasingly apparent that the Wzy-dependent and ABC transporter-dependent pathways are widespread in bacteria. Similar systems have been reported for capsular and extracellular polysaccharides. To date, the newly described third pathway, the synthase-dependent pathway, has only been characterized for the 0:54 OPS of Salmonella, but it resembles the synthetic process for bacterial cellulose, chitin, and possibly certain streptococcal capsular polysaccharides. The critical feature of this pathway is a unique glycosyl transferase, which is proposed to catalyze a vectorial polymerization, sequentially adding monosaccharide substituents while simultaneously extruding the nascent polymer across the plasma membrane.
Natural Products Structures and Analysis of the Cerrado Flora in Goiás
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Lucilia Kato, Vanessa Gisele Pasqualotto Severino, Aristônio Magalhães Teles, Aline Pereira Moraes, Vinicius Galvão Wakui, Núbia Alves Mariano Teixeira Pires Gomides, Rita de Cássia Lemos Lima, Cecilia Maria Alves de Oliveira
The RFC indicates how a given species can be highlighted in relation to the others (Begossi, 1996), indicating, however, its importance to the community under study. RFC may be derived from the formula RFC = FC/N (0 < RFC < 1).
Prognostic biomarker replication factor C subunit 5 and its correlation with immune infiltrates in acute myeloid leukemia
Published in Hematology, 2022
Wang-jun Li, Dong-wei Wu, Yi-feng Zhou, Chen-wei Zhang, Xiao-wei Liao
Replication factor C (RFC) is a five-subunit complex comprised of RFC1 (140 kDa), RFC2 (40 kDa), RFC3 (38 kDa), RFC4 (37 kDa), and RFC5 (36 kDa) [9], which are highly conserved in all eukaryotes [10–12]. The five subunits have high homology to each other [13]. It has been reported that RFC can load proliferating cell nuclear antigen and DNA polymerase onto a template-primer junction in an ATP-dependent manner [14]. Besides, RFC represents a crucial role in checkpoint control, DNA polymerase switching, and DNA repair [15–17]. As a subunit of RFC, RFC5 is involved in cell cycle regulation, nucleotide excision, DNA double helix damage, and repairing mismatches [18, 19]. A previous study showed significant RFC5 upregulation in prostate cancer compared to normal prostate tissues [20]. In cervical cancer C33A cells, overexpression of SIX1 upregulated the RFC5 expression [21]. Additionally, the elevated RFC5 expression in tumor tissues prior to isolated hepatic perfusion is significantly related to poor prognosis [22]. However, little is known about the connection of RFC5 with AML.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
As opposed to the small base lesions corrected using BER, nucleotide excision repair (NER) removes the bulky DNA lesions caused by UV light, environmental mutagens, and cancer chemotherapy adducts [8]. Once the damage is recognized, transcription factor II H (THFIIH) and XPG are recruited to the site to act as helicases and unwind the DNA. XPG and XPF-ERCC1 then act as endonucleases to cut the DNA on either side of the damage, removing a single strand of 25–30 nucleotides. Proliferating cell nuclear antigen is loaded onto the DNA strand by replication factor C allowing DNA polymerases to copy the undamaged strand. Finally, DNA ligase I and flap endonuclease 1 seal the nicks in the repaired DNA [8]. Poly (ADP-ribose) polymerases (PARPs) are enzymes which play a role in BER and NER, as well as single stranded break repair [9]. PARP binds to sites of DNA strand breaks to facilitate access of the respective repair enzymes to the site [9]. PARP inhibition has shown synthetic lethality with BRCA mutations in the clinical and preclinical setting [9].
Development of new agents for peripheral T-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2019
Yuta Ito, Shinichi Makita, Kensei Tobinai
Pralatrexate (10-propargyl-10-deazaaminopterin) is an anti-folate agent that inhibits dihydrofolate reductase (DHFR). As DHFR is a key enzyme in the conversion of dihydrofolate to tetrahydrofolate, which is required for the synthesis of thymidylate and purine nucleotides, the inhibition of DHFR blocks cell division in the S phase [7]. Compared with other anti-folate agents, such as methotrexate, high intracellular concentrations of pralatrexate can be reached owing to its high affinity for the reduced folate carrier-1 (RFC-1) that takes pralatrexate into intracellular space. This higher affinity for RFC-1 may be associated with the greater selectivity of pralatrexate for tumor cells because many tumors overexpress RFC-1. Furthermore, intracellular pralatrexate is metabolized into a polyglutamated form by folylpolyglutamate synthetase; polyglutamates are preferentially retained in the intracellular space, which makes them less susceptible to efflux-based drug resistance [8].