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Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
MTX inhibits the action of the FA reductase, which is responsible for conversion of FA to tetrahydrofolic acid [362, 363]. In the absence of tetrahydrofolic acids, DNA, RNA, and proteins cannot be synthesized, leading to blockage of cell division. Hydroxyurea (hyhdroxycarbamide) reduces production of deoxyribonucleotides through inhibition of the enzyme ribonucleotidereductase [361–366]. This enzyme catalyzes the reduction of ribonucleotide into their corresponding deoxyribonucleotides, which are required for DNA synthesis. 5-FU, a thymidylate synthase inhibitor, is widely used in the treatment of patients with breast or gastrointestinal tract cancer. Interrupting the action of this enzyme blocks the synthesis of pyrimidine thymidine, which is a nucleoside required for DNA replication, in the S phase of the cell cycle [367]. Thymidylate synthase converts deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP), which is crucial in production of pyrimidine base for synthesis of DNA; thus, it is a viable target for cancer chemotherapy [367]. 5-FU causes a scarcity of dTMP. Therefore, rapidly dividing cancer cells undergo apoptosis via thymine-less death. 5-FU can arrest unlimited proliferation of cancer cells and also lead to production of faulty rRNA [368, 369]. The immunosuppressive drug 6-MP alters the synthesis and function of DNA and RNA by inhibiting purine nucleotide synthesis and metabolism and interferes with nucleotide interconversion and glycoprotein synthesis [370, 371].
Bowen Disease
Published in Nilton Di Chiacchio, Antonella Tosti, Therapies for Nail Disorders, 2020
Topical fluorouracil (5-FU), a thymidylate synthase inhibitor that halts DNA synthesis, although not approved for the treatment of BD, is a commonly recognized treatment option for BD. Topically applied 5-FU is commercially available in a 5% cream; application generally consists of once or twice daily application for 2–8 weeks depending on BD location.24,30 With this regimen, small randomized trials have found clinical cure rates of 48%–56% for cutaneous BD.24,30 A systematic review in 2013 found that 5-FU is equivalent to cryotherapy for cutaneous BD.31 One case series describes seven cases BD of the nail bed and periungual area, in which six cases were treated by MMS, and one treated with 5-FU.32 Two of six lesions recurred after MMS, 1 and 2 years after surgery, while the lesion treated with topical 5-FU had residual BD found at 6 weeks post-treatment and subsequently underwent MMS for definitive treatment.32 The most frequent side effects of 5-FU include erythema, pain, irritant dermatitis, and pruritus.33 Patient adherence should be considered when prescribing a topical therapy, as daily application is usually required.
Pharmacokinetics of intraperitoneal cytotoxic drug therapy
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Since their introduction in 1957 by Heidelberger et al., the fluorinated pyrimidines have been successfully used for a wide variety of tumors and are still an essential component of all successful gastrointestinal cancer chemotherapy regimens [84,85]. This thymidylate synthase inhibitor binds covalently with the enzyme and prevents the formation of thymidine monophosphate, the DNA nucleoside precursor. Also 5-FU by its metabolites 5-fluoro-uridine diphosphate and 5-fluoro-uridine triphosphate gets incorporated in RNA, resulting in a second cytotoxic pathway. The action of 5-fluorouracil is therefore cell-cycle-specific. These characteristics limit the use of IP 5-fluorouracil to EPIC [86–89]. Minor augmentation of 5-fluorouracil by mild hyperthermia is reported [31]. 5-Fluorouracil is not chemically compatible with other drugs in a mixed solution for infusion or instillation.
Orally delivered targeted nanotherapeutics for the treatment of colorectal cancer
Published in Expert Opinion on Drug Delivery, 2020
Xueqing Zhang, Heliang Song, Brandon S.B. Canup, Bo Xiao
Liposomes are spherical vehicles, which are made from various lipid components with hydrophobic lipid bilayer and aqueous internal cavity. These unique features make liposomes the most common drug delivery system for the delivery of both hydrophobic and hydrophilic agents. In a phase I clinical trial, 14 advanced CRC patients were treated with oxaliplatin and OSI-7904 L (liposomal formulation of a potential thymidylate synthase inhibitor), which resulted in disease stabilization in 11 of 12 patients, and 2 partial disease responses [24]. In a phase II clinical trial of a liposomal DACH platinum, 1 of 18 patients was confirmed as partial disease responses after 6 cycles of treatments [25]. 11 of 15 CRC patients receiving the treatment of CPX-1, a liposomal formulation of irinotecan and floxuridine, achieved disease control [26]. In addition to these clinical trials, liposomal formulations of irinotecan, Id2 siRNA, and CUR showed promising therapeutic outcomes based on mice models [27].
Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer
Published in Acta Oncologica, 2020
Anne Dyhl-Polk, Merete Vaage-Nilsen, Morten Schou, Kirsten Kjeldgaard Vistisen, Cecilia Margareta Lund, Thomas Kümler, Jon Michael Appel, Dorte Lisbet Nielsen
Alternative treatment options in patients with colorectal cancer include UFT, S-1 or raltitrexed. In UFT and S-1, the 5-FU prodrug, tegafur, are combined with a dihydropyrimidine dehydrogenase (DPD) inhibitor that reduces the degradation of 5-FU to fluorobetaalanine [39]. Since fluorobetaalanine may be involved in the cardiotoxic effects from fluoropyrimidines [40], DPD inhibition should result in lower incidences of cardiotoxicity. For UFT, lower incidences of cardiotoxicity (1%) have been reported [41], but there are few published data regarding the cardiotoxicity from S-1. Yet, a case series of seven patients whom were successfully treated with S-1 after cardiotoxicity induced by capecitabine has been published [42]. The thymidylate synthase inhibitor, raltitrexed, is an alternative in patients with advanced colorectal cancer. In 42 patients with cardiotoxicity induced by 5-FU or capecitabine, no further cardiac events were reported during treatment with raltitrexed [43]. However, raltitrexed has been associated with a high mortality rate (2–6%) [44].
Design, synthesis, molecular modelling, and biological evaluation of novel substituted pyrimidine derivatives as potential anticancer agents for hepatocellular carcinoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Naglaa Mohamed Ahmed, Mahmoud Youns, Moustafa Khames Soltan, Ahmed Mohammed Said
Pyrimidine ring is one of the mostly used heterocyclic scaffolds in medicinal chemistry. Pyrimidine derivatives have been well recognised for their therapeutic applications i.e. antiviral5,6, antibacterial7,8, antifungal9, anti-inflammatory10, COX-2 inhibitors11, antioxidant12, antithyroid13, anticonvulsant14, and anti-diabetic15. Pyrimidine ring is also an integral part of DNA nucleic acid composition. Various drugs containing pyrimidine nucleus are being used as potent anticancer agents through different mechanisms of action i.e. 5-Fluorouracil® (5-FU) I as thymidylate synthase inhibitor16, Merbarone®II as DNA topoisomerase II (topoII) catalytic inhibitor17, Ceritinib (LDK378) III as anaplastic lymphoma kinase (ALK) inhibitor18, Dasatinib IV as multi-targeted of Bcr-Abl and Src family kinases inhibitor apoptosis inducer19, Imatinib V as a receptor tyrosine kinase (TKI) inhibitor20, Ibrutinib (IBR) VI as Bruton’s tyrosine kinase (BTK) inhibitor21, Ruxolitinib (INC424) VII as Janus kinase (JAK) inhibitor22 and Nilotinib VIII as tyrosine kinase inhibitor and apoptosis inducer23 (Figure 1).