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Monographs of Topical Drugs that Have Caused Contact Allergy/Allergic Contact Dermatitis
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Fluorouracil (5-FU) is an antimetabolite fluoropyrimidine analog of the nucleoside pyrimidine with antineoplastic activity. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Fluorouracil is indicated for the topical treatment of multiple actinic (solar) keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including of the colon, esophagus, rectum, breast, biliary tract, stomach, head and neck, cervix, pancreas, renal cell cancer and carcinoid (1).
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].
Mechanisms of Resistance to Antineoplastic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Philip J. Vickers, Alan J. Townsend, Kenneth H. Cowan
Another example of an altered target site leading to drug resistance has been demonstrated in cells which expressed a mutant thymidylate synthase. In these cells, resistance to 5-FU is associated with a decrease in the affinity of thymidylate synthase for the activated form of the drug (FdUMP).83
Capecitabine in treating patients with advanced, persistent, or recurrent cervical cancer: an active and safe option?
Published in Expert Opinion on Drug Safety, 2021
Federica Tomao, Giuseppe Caruso, Lucia Musacchio, Violante Di Donato, Maria Cristina Petrella, Monica Verrico, Silverio Tomao, Pierluigi Benedetti Panici, Ludovico Muzii, Innocenza Palaia
Capecitabine is an oral pro-drug that is enzymatically metabolized by thymidine phosphorylase (TP) to cytotoxic 5-fluorouracil (5-FU). The latter inhibits thymidylate synthase (TS) and thus the synthesis of thymidine monophosphate (dTMP), the active form of thymidine required for DNA de novo synthesis [30]. The dihydropyrimidine dehydrogenase (DPD) is another enzyme involved in the 5-FU metabolic pathway, which catabolizes 5-FU to inactive dihydrofluorouracil in the liver, resulting in increased urinary excretion (Figure 1) [31]. Basically, the TP/DPD ratio biologically determines the intracellular 5-FU concentration [32]. Extensive studies have associated both profound and partial DPD deficiency (3–5% of the general population) with severe, unanticipated toxicities after 5-FU administration, including mucositis, hair loss, diarrhea, neutropenia, skin rash, and neurologic toxicities [33]. Research on the molecular basis behind DPD deficiency has highlighted various sequence variants of the DPYD gene, hence screening patients for DPD deficiency prior to 5 FU or capecitabine administration should be recommended [34].
Reducing unpleasant side effects of topical 5-Fluorouracil treatment for actinic keratosis: a randomized controlled trial
Published in Journal of Dermatological Treatment, 2020
Melody Maarouf, Bryan W. Kromenacker, Eric S. Brucks, Aleksi Hendricks, Vivian Y. Shi
Actinic keratosis (AK) carries a 0.25–16% risk of progression to squamous cell carcinoma, warranting prophylactic treatment (1). Topical therapy for ‘field cancerization,’ or diffuse AK burden (2), treats clinical and occult lesions (2,3). 5-Fluorouracil (5-FU) inhibits thymidylate synthetase, a DNA precursor enzyme. Inhibition of DNA synthesis in dysplastic cells causes apoptosis (1), resulting in an inflammatory response characterized by erythema, blistering, necrosis with erosion, and subsequent reepithelialization (2). Complete clearance with topical 5-FU treatment can be seen in up to 90% of patients without extensive hyperkeratotic AKs who can tolerate the side effects (4,5). Unfortunately, nearly all patients experience some degree of pain, itching, burning, irritation, inflammation, dryness, swelling, and tenderness, which may take several weeks to subside. These unpleasant yet unavoidable side effects are the primary reason for patient noncompliance (6) and dissatisfaction (7).
Design, synthesis and in vitro antiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Zohor Mohammad Mahdi Alzhrani, Mohammad Mahboob Alam, Thikryat Neamatallah, Syed Nazreen
Despite the availability of various chemotherapeutic agents, cancer is the second highest cause of deaths next to cardiovascular diseases.1,2 Thymidylate synthase (TS) has become an area of interest in cancer chemotherapy due to their important role in DNA biosynthesis.3,4 TS is responsible for the formation of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) which is further phosphorylated to triphosphate group (dTTP), a direct precursor for DNA synthesis.5–7 TS inhibition causes inhibition of thymidylate biosynthesis which in turn causes cessation of cell growth and proliferation.8,9 Research on TS has been going on since many years, but still it is a challenge for medicinal chemists to develop new, safe and effective chemotherapeutic agents as TS inhibitor.