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Yan S, Hu X, Wu Y, Ye W, Zhu Y, He Y, Zhan F, Wu W, Ma Z. ITGA4 Contributes to 5-Fluorouracil Resistance by Up-Regulating PI3K/AKT Signaling: Evidence from Network Pharmacology, Molecular Docking and Experimental Verification. Drug Des Devel Ther 2025; 19:4105-4122. [PMID: 40416795 PMCID: PMC12103172 DOI: 10.2147/dddt.s474421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 05/13/2025] [Indexed: 05/27/2025] Open
Abstract
Objective 5-Fluorouracil (5-FU) is a mainstream drug used in chemotherapy and chemoradiotherapy regimens for the clinical treatment of malignancies, such as gastric cancer (GC), colorectal cancer, and breast cancer. However, the molecular mechanism of action of 5-FU in GC has not yet been studied using a network pharmacology approach. Methods The mechanism of action of 5-FU in GC was determined using a network pharmacology technique, and our findings were confirmed by various computational approaches and experimental tests using the GeneCards database, ChEMBL database, STRING database, molecular docking, molecular dynamics simulation, DAVID, GEPIA, Kaplan‒Meier Plotter, CCK-8 assays, colony formation experiments, cell proliferative assay, apoptosis assays, wound-healing assays, Real-time PCR and Western blot tests. Results A total of 21 shared and 13 potential targets were identified using PPI network analysis. Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses indicated that the PI3K/AKT signaling pathway may be a significant pathway. Combined with molecular docking and database verification, F10, NR3C1, DHFR, CA2, BCHE, ACHE, and ITGA4 were identified as candidate core genes. Moreover, the experimental results illustrated that ITGA4 induces 5-FU resistance by up-regulating PI3K/AKT signaling. Conclusion Network pharmacology is a feasible scientific research strategy for revealing the multitarget-multipathway role of 5-FU in the treatment of GC and provides ITGA4-based new ideas and therapeutic strategy to overcome 5-FU resistance for GC treatment.
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Affiliation(s)
- Sicheng Yan
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
| | - Xiaomeng Hu
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
| | - Yan Wu
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
| | - Wangfang Ye
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
| | - Yuehong Zhu
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
| | - Yuxuan He
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
| | - Fuyuan Zhan
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, People’s Republic of China
| | - Wei Wu
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer of Huzhou, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
| | - Zhihong Ma
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, People’s Republic of China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, People’s Republic of China
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Mielke H, Algharably EAE, Gundert-Remy U. 5-Fluorouracil Toxicity: Revisiting the Relevance of Pharmacokinetic Parameters. Pharmaceuticals (Basel) 2025; 18:653. [PMID: 40430472 PMCID: PMC12114802 DOI: 10.3390/ph18050653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/08/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: 5-fluorouracil (5-FU) is used in the treatment of solid cancer types. Because of its narrow therapeutic window, drug monitoring is recommended. We were confronted to answer a question on the relevance of concentration as opposed to the area under the plasma concentration-time curve (AUC) to predict toxicity when we had to assess the case of a patient who died after an erroneously high infusion rate. Methods: We used physiologically-based pharmacokinetic modeling (PBPK) to simulate the concentration-time profile of 5-FU data on doses, dosing schedules and life-threatening toxicity for both the patient in question as well as data from the literature. Furthermore, steady-state 5-FU concentrations were calculated from an additional set of data found in the literature on AUCs and non-life-threatening toxicity. Results: The model predictions matched well with experimental data, confirming the suitability of the model. Life-threatening toxicity was related to a concentration above 6 mg/L, whereas non-life-threatening toxicity was low at concentrations less than 3 mg/L but steeply increased between 3 and 4 mg/L. Data analysis supported by a decision algorithm suggests that the 5-FU steady-state plasma concentration is a better toxicity predictor than the AUC. Conclusions: We recommend monitoring the concentration one hour after infusion starts when about 50% of the steady state is reached in patients for whom higher doses are clinically considered relevant. Monitoring the concentration one hour after starting the infusion has the advantage that dose correction could be made early before toxicity can be observed.
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Affiliation(s)
- Hans Mielke
- Department of Exposure, German Federal Institute for Risk Assessment (BfR), Max-Dohrn 8–10, 10589 Berlin, Germany;
| | - Engi Abd Elhady Algharably
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Charitéplatz 1, 10117 Berlin, Germany;
| | - Ursula Gundert-Remy
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Charitéplatz 1, 10117 Berlin, Germany;
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Zhang X, Dong T, Li X, Xu C, Chen F, Wang S, Wang X. Design, Synthesis, and Evaluation of Doxifluridine Derivatives as Nitroreductase-Responsive Anticancer Prodrugs. Molecules 2024; 29:5077. [PMID: 39519718 PMCID: PMC11547703 DOI: 10.3390/molecules29215077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/23/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Antimetabolite antitumor drugs interfere with nucleic acid and DNA synthesis, causing cancer cell death. However, they also affect rapidly dividing normal cells and cause serious side effects. Doxifluridine (5'-deoxy-5-fluorouridine [5'-DFUR]), a 5-fluorouracil (5-FU) prodrug converted to 5-FU by thymidine phosphorylase (TP), exerts antitumor effects. Since TP is distributed in tumor and normal tissues, 5'-DFUR features side effects. Here we designed a series of novel 5'-DFUR derivatives based on high nitroreductase (NTR) levels in the hypoxic microenvironment of tumor tissues by introducing nitro-containing moieties into the 5'-DFUR structure. These derivatives exert their antitumor effects by producing 5-FU under the dual action of TP and NTR in the tumor microenvironment. The derivatives were synthesized and their stability, release, and cytotoxicity evaluated in vitro and antitumor activity evaluated in vivo. Compound 2c, featuring nitrofuran fragments, was stable in phosphate-buffered saline and plasma at different pH values and reduced rapidly in the presence of NTR. The in vitro cytotoxicity evaluation indicated that compound 2c showed excellent selectivity in the MCF-7 and HT29 cell lines. Moreover, it exhibited antitumor effects comparable to those of 5'-DFUR in vivo without significant toxic side effects. These results suggest that compound 2c is a promising antitumor prodrug.
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Affiliation(s)
| | | | | | | | | | - Shiben Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.Z.); (T.D.); (X.L.); (C.X.); (F.C.)
| | - Xuekun Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.Z.); (T.D.); (X.L.); (C.X.); (F.C.)
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Hashimoto Y, Yoshida Y, Yamada T, Yoshimatsu G, Yoshimura F, Hasegawa S. Association Between Changes in Plasma Capecitabine Concentrations and Adverse Events in the Treatment of Colorectal Cancer. Cureus 2024; 16:e71341. [PMID: 39534818 PMCID: PMC11555300 DOI: 10.7759/cureus.71341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
Background Therapeutic drug monitoring (TDM) is an effective approach to improving the efficacy of drugs with a narrow therapeutic index and high toxicity. TDM-guided dosing of 5-fluorouracil (5-FU) has been shown to result in superior efficacy and fewer adverse events compared to body surface area (BSA)-based dosing. Therefore, accurate measurement of plasma 5-FU concentrations after capecitabine administration is necessary. Capecitabine is a prodrug of 5-FU and is metabolized to 5-FU in multiple steps in the gastrointestinal tract, liver, and within tumors. To solve the problem of frequent blood draws for TDM, we reduced the number of blood draws to two and examined whether changes in 5-FU concentration correlated with adverse events. Methods This study investigated the relationship between the changes in plasma 5-FU concentrations after one and two hours of capecitabine administration in 36 patients and adverse events based on drug concentrations determined after adding 5-NU to the plasma samples. Concentration gradients and adverse events were estimated using the Mann-Whitney test. Results The median one- and two-hour plasma 5-FU concentrations were 67.5 (range 5-307) and 85.5 (range 19-246) ng/mL, respectively. The plasma 5-FU concentration gradient, defined as the difference between the one- and two-hour concentrations, was significantly higher in patients with diarrhea and nausea (p = 0.0234 and p = 0.0409, respectively). Conclusion The high plasma 5-FU concentration gradient suggests rapid degradation of 5-FU into its metabolites, which may lead to predict intestinal mucosal damage, diarrhea, and nausea.
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Affiliation(s)
| | - Yoichiro Yoshida
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
| | - Teppei Yamada
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
| | - Gumpei Yoshimatsu
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
| | | | - Suguru Hasegawa
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
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Mafi A, Hedayati N, Milasi YE, Kahkesh S, Daviran M, Farahani N, Hashemi M, Nabavi N, Alimohammadi M, Rahimzadeh P, Taheriazam A. The function and mechanism of circRNAs in 5-fluorouracil resistance in tumors: Biological mechanisms and future potential. Pathol Res Pract 2024; 260:155457. [PMID: 39018926 DOI: 10.1016/j.prp.2024.155457] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/19/2024]
Abstract
5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.
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Affiliation(s)
- Alireza Mafi
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Minoo Daviran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najma Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Meng J, Wang ZG, Zhao X, Wang Y, Chen DY, Liu DL, Ji CC, Wang TF, Zhang LM, Bai HX, Li BY, Liu Y, Wang L, Yu WG, Yin ZT. Silica nanoparticle design for colorectal cancer treatment: Recent progress and clinical potential. World J Clin Oncol 2024; 15:667-673. [PMID: 38946830 PMCID: PMC11212613 DOI: 10.5306/wjco.v15.i6.667] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 03/18/2024] [Accepted: 04/24/2024] [Indexed: 06/24/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.
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Affiliation(s)
- Jin Meng
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Zhi-Gang Wang
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Xiu Zhao
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Ying Wang
- Acupuncture and Tuina College, Liaoning University of Traditional Chinese Medicine, Shenyang 110032, Liaoning Province, China
| | - De-Yu Chen
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - De-Long Liu
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Cheng-Chun Ji
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Tian-Fu Wang
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Li-Mei Zhang
- Department of Neurology, Central Hospital of Dalian University of Technology, Dalian 116001, Liaoning Province, China
| | - Hai-Xia Bai
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Bo-Yang Li
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Yuan Liu
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Lei Wang
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Wei-Gang Yu
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
| | - Zhi-Tao Yin
- Department of Anorectal Disease, Shenyang Coloproctology Hospital, Shenyang 110000, Liaoning Province, China
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Qu M, Chen J, Xu B, Shi Q, Zhao S, Wang Z, Li Z, Ma B, Xu H, Ye Q, Xie J. Assessing genotoxic effects of chemotherapy agents by a robust in vitro assay based on mass spectrometric quantification of γ-H2AX in HepG2 cells. Front Pharmacol 2024; 15:1356753. [PMID: 38962306 PMCID: PMC11219945 DOI: 10.3389/fphar.2024.1356753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
Chemotherapy has already proven widely effective in treating cancer. Chemotherapeutic agents usually include DNA damaging agents and non-DNA damaging agents. Assessing genotoxic effect is significant during chemotherapy drug development, since the ability to attack DNA is the major concern for DNA damaging agents which relates to the therapeutic effect, meanwhile genotoxicity should also be evaluated for chemotherapy agents' safety especially for non-DNA damaging agents. However, currently applicability of in vitro genotoxicity assays is hampered by the fact that genotoxicity results have comparatively high false positive rates. γ-H2AX has been shown to be a bifunctional biomarker reflecting both DNA damage response and repair. Previously, we developed an in vitro genotoxicity assay based on γ-H2AX quantification using mass spectrometry. Here, we employed the assay to quantitatively assess the genotoxic effects of 34 classic chemotherapy agents in HepG2 cells. Results demonstrated that the evaluation of cellular γ-H2AX could be an effective approach to screen and distinguish types of action of different classes of chemotherapy agents. In addition, two crucial indexes of DNA repair kinetic curve, i.e., k (speed of γ-H2AX descending) and t50 (time required for γ-H2AX to drop to half of the maximum value) estimated by our developed online tools were employed to further evaluate nine representative chemotherapy agents, which showed a close association with therapeutic index or carcinogenic level. The present study demonstrated that mass spectrometric quantification of γ-H2AX may be an appropriate tool to preliminarily evaluate genotoxic effects of chemotherapy agents.
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Affiliation(s)
- Minmin Qu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Jia Chen
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Bin Xu
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Qinyun Shi
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Shujing Zhao
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Zhaoxia Wang
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Zhi Li
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Bo Ma
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Hua Xu
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Jianwei Xie
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
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Mironiuk-Puchalska E, Karatsai O, Żuchowska A, Wróblewski W, Borys F, Lehka L, Rędowicz MJ, Koszytkowska-Stawińska M. Development of 5-fluorouracil-dichloroacetate mutual prodrugs as anticancer agents. Bioorg Chem 2023; 140:106784. [PMID: 37639758 DOI: 10.1016/j.bioorg.2023.106784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/31/2023] [Accepted: 08/11/2023] [Indexed: 08/31/2023]
Abstract
5-Fluorouracil (5-FU) is one of the most widely applied chemotherapeutic agents with a broad spectrum of activity. However, despite this versatile activity, its use poses many limitations. Herein, novel derivatives of 5-FU and dichloroacetic acid have been designed and synthesized as a new type of codrugs, also known as mutual prodrugs, to overcome the drawbacks of 5-FU and enhance its therapeutic efficiency. The stability of the obtained compounds has been tested at various pH values using different analytical techniques, namely HPLC and potentiometry. The antiproliferative activity of the new 5-FU derivatives was assessed in vitro on SK-MEL-28 and WM793 human melanoma cell lines in 2D culture as well as on A549 human lung carcinoma, MDA-MB-231 breast adenocarcinoma, LL24 normal lung tissue, and HMF normal breast tissue as a multicellular 3D spheroid model cultured in standard (static) conditions and with the use of microfluidic systems, which to a great extent resembles the in vivo environment. In all cases, new mutual prodrugs showed a higher cytotoxic activity toward cancer models and lower to normal cell models than the parent 5-FU itself.
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Affiliation(s)
- Ewa Mironiuk-Puchalska
- Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland.
| | - Olena Karatsai
- Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology Polish Academy of Science, 3 Pasteur St., 02-093-Warsaw, Poland
| | - Agnieszka Żuchowska
- Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland
| | - Wojciech Wróblewski
- Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland
| | - Filip Borys
- Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland
| | - Lilya Lehka
- Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology Polish Academy of Science, 3 Pasteur St., 02-093-Warsaw, Poland
| | - Maria Jolanta Rędowicz
- Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology Polish Academy of Science, 3 Pasteur St., 02-093-Warsaw, Poland
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Laures N, Konecki C, Brugel M, Giffard AL, Abdelli N, Botsen D, Carlier C, Gozalo C, Feliu C, Slimano F, Djerada Z, Bouché O. Impact of Guidelines Regarding Dihydropyrimidine Dehydrogenase (DPD) Deficiency Screening Using Uracil-Based Phenotyping on the Reduction of Severe Side Effect of 5-Fluorouracil-Based Chemotherapy: A Propension Score Analysis. Pharmaceutics 2022; 14:pharmaceutics14102119. [PMID: 36297556 PMCID: PMC9610761 DOI: 10.3390/pharmaceutics14102119] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/07/2022] Open
Abstract
Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal to or greater than 16 ng/mL. This matched retrospective study assessed the impact of DPD screening on the reduction of severe side effects and on the management of DPD-deficient patients. Using a propensity score, we balanced the factors influencing 5-Fluorouracil (5-FU) toxicity. Then, the severity scores (G3 and G4 severity as well as their frequency) of patients who did not benefit from DPD screening were compared with those of patients who benefited from DPD screening for each treatment cycle (from 1 to 4). Among 349 screened patients, 198 treated patients were included. Among them, 31 (15.7%) had DPD deficiency (median uracilemia 19.8 ng/mL (range: 16.1−172.3)). The median toxicity severity score was higher in the unscreened group for each treatment cycle (0 vs. 1, p < 0.001 at each cycle from 1 to 4) as well as the cumulative score during all courses of treatment (p = 0.028). DPD-deficient patients received a significantly lower dose of 5-FU (p < 0.001). This study suggests that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients.
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Affiliation(s)
- Nicolas Laures
- Department of Gastroenterology and Digestive Oncology, CHU Reims, University of Reims Champagne-Ardenne (URCA), 51100 Reims, France
| | - Céline Konecki
- Department of Medical Pharmacology, University of Reims Champagne-Ardenne (URCA), HERVI EA3801, 51097 Reims, France
- Department of Pharmacology and Toxicology, CHU Reims, 51100 Reims, France
| | - Mathias Brugel
- Department of Gastroenterology and Digestive Oncology, CHU Reims, University of Reims Champagne-Ardenne (URCA), 51100 Reims, France
- Department of Hepato-Gastroenterology and Digestive Oncology, Centre Hospitalier Auban-Moët, 51200 Epernay, France
| | - Anne-Lise Giffard
- Department of Gastroenterology and Digestive Oncology, CHU Reims, University of Reims Champagne-Ardenne (URCA), 51100 Reims, France
| | - Naceur Abdelli
- Department of Hepato-Gastroenterology and Digestive Oncology, Centre Hospitalier de Chalons en Champagne, 51000 Chalons en Champagne, France
| | - Damien Botsen
- Department of Gastroenterology and Digestive Oncology, CHU Reims, University of Reims Champagne-Ardenne (URCA), 51100 Reims, France
| | - Claire Carlier
- Department of Gastroenterology and Digestive Oncology, CHU Reims, University of Reims Champagne-Ardenne (URCA), 51100 Reims, France
| | - Claire Gozalo
- Department of Medical Pharmacology, University of Reims Champagne-Ardenne (URCA), HERVI EA3801, 51097 Reims, France
- Department of Pharmacology and Toxicology, CHU Reims, 51100 Reims, France
| | - Catherine Feliu
- Department of Medical Pharmacology, University of Reims Champagne-Ardenne (URCA), HERVI EA3801, 51097 Reims, France
- Department of Pharmacology and Toxicology, CHU Reims, 51100 Reims, France
| | - Florian Slimano
- Department of Pharmacy, CHU Reims, University of Reims Champagne-Ardenne (URCA), 51100 Reims, France
| | - Zoubir Djerada
- Department of Medical Pharmacology, University of Reims Champagne-Ardenne (URCA), HERVI EA3801, 51097 Reims, France
- Department of Pharmacology and Toxicology, CHU Reims, 51100 Reims, France
- Correspondence:
| | - Olivier Bouché
- Department of Medical Pharmacology, University of Reims Champagne-Ardenne (URCA), HERVI EA3801, 51097 Reims, France
- Department of Pharmacology and Toxicology, CHU Reims, 51100 Reims, France
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Seidi F, Zhong Y, Xiao H, Jin Y, Crespy D. Degradable polyprodrugs: design and therapeutic efficiency. Chem Soc Rev 2022; 51:6652-6703. [PMID: 35796314 DOI: 10.1039/d2cs00099g] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Prodrugs are developed to increase the therapeutic properties of drugs and reduce their side effects. Polyprodrugs emerged as highly efficient prodrugs produced by the polymerization of one or several drug monomers. Polyprodrugs can be gradually degraded to release therapeutic agents. The complete degradation of polyprodrugs is an important factor to guarantee the successful disposal of the drug delivery system from the body. The degradation of polyprodrugs and release rate of the drugs can be controlled by the type of covalent bonds linking the monomer drug units in the polymer structure. Therefore, various types of polyprodrugs have been developed based on polyesters, polyanhydrides, polycarbonates, polyurethanes, polyamides, polyketals, polymetallodrugs, polyphosphazenes, and polyimines. Furthermore, the presence of stimuli-responsive groups, such as redox-responsive linkages (disulfide, boronate ester, metal-complex, and oxalate), pH-responsive linkages (ester, imine, hydrazone, acetal, orthoester, P-O and P-N), light-responsive (metal-complex, o-nitrophenyl groups) and enzyme-responsive linkages (ester, peptides) allow for a selective degradation of the polymer backbone in targeted tumors. We envision that new strategies providing a more efficient synergistic therapy will be developed by combining polyprodrugs with gene delivery segments and targeting moieties.
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Affiliation(s)
- Farzad Seidi
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources and International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing 210037, China. .,Department of Materials Science and Engineering, School of Molecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong 21210, Thailand.
| | - Yajie Zhong
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources and International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing 210037, China.
| | - Huining Xiao
- Department of Chemical Engineering, University of New Brunswick, Fredericton, New Brunswick, E3B 5A3, Canada
| | - Yongcan Jin
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources and International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing 210037, China.
| | - Daniel Crespy
- Department of Materials Science and Engineering, School of Molecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong 21210, Thailand.
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11
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Huang J, Wu Z, Xu J. Effects of Biofilm Nano-Composite Drugs OMVs-MSN-5-FU on Cervical Lymph Node Metastases From Oral Squamous Cell Carcinoma. Front Oncol 2022; 12:881910. [PMID: 35515126 PMCID: PMC9062107 DOI: 10.3389/fonc.2022.881910] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
This work was developed to the effects of biofilm composite nano-drug delivery system (OMVs-MSN-5-FU) on lymph node metastasis from oral squamous cell carcinoma. Mesoporous silica nanoparticles loaded with 5-FU (MSN-5-FU) were prepared first. Subsequently, the outer membrane vesicles (OMV) of Escherichia coli were collected to wrap MSN-5-FU, and then OMVs-MSN-5-FU was prepared. It was then immersed in artificial gastric juice and artificial intestinal juice to explore the drug release rate. Next, the effects of different concentrations of the nano-drug delivery systems on the proliferation activity of oral squamous carcinoma cell line KOSC-2 cl3-43 were analyzed. Tumor-bearing nude mice models were prepared by injecting human tongue squamous cell carcinoma cells Tca8113 into BALB/c-nu nude mice. They were injected with the OMVs-MSN-5-FU nano drug carrier system, and peri-carcinoma tissue and cervical lymph node tissue were harvested to observe morphological changes by Hematoxylin - eosin (HE) staining. The scanning electron microscope (SEM) results showed that all MSN, MSN-5-FU, OMV, and OMV-MSN-5-FU were spherical and uniformly distributed, with particle sizes of about 60nm, 80nm, 90nm, and 140nm, respectively. Among them, OMV had a directional core-shell structure. The cumulative drug release rates of artificial gastric juice in 48 hours were 61.2 ± 2.3% and 26.5 ± 3.1%, respectively. The 48 hours cumulative drug release rates of artificial intestinal juice were 70.5 ± 6.3% and 32.1 ± 3.8%, respectively. The cumulative release of MSN-5-FU was always higher than OMV-MSN-5-FU. The cumulative release of MSN-5-FU was always higher than OMV-MSN-5-FU. After injection of OMVS-MSN-5-FU, the number of cancer cells was significantly reduced and cervical lymph node metastasis was significantly controlled. HE staining results showed that OMVS-MSN-5-FU injection reduced the number of stained cells. Dense lymphocytes were clearly observed in the cortex of neck lymphocytes. The OMVs-MSN-5-FU drug delivery system can slow down the drug release rate, significantly inhibit the proliferation activity of oral squamous cancer cells, and control the metastasis of cancer cells to cervical lymph nodes.
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Affiliation(s)
- Jian Huang
- Department of Oral and Maxillofacial Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Zhiyuan Wu
- Department of Oral and Maxillofacial Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Junwu Xu
- Department of Oral and Maxillofacial Surgery, Fujian Provincial Hospital, Fuzhou, China
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12
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Grumetti L, Lombardi R, Iannelli F, Pucci B, Avallone A, Di Gennaro E, Budillon A. Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors. Cancers (Basel) 2022; 14:cancers14030695. [PMID: 35158962 PMCID: PMC8833539 DOI: 10.3390/cancers14030695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Fluoropyrimidines represent the backbone of many combination chemotherapy regimens for the treatment of solid cancers but are still associated with toxicity and mechanisms of resistance. In this review, we focused on the epigenetic modifiers histone deacetylase inhibitors (HDACis) and on their ability to regulate specific genes and proteins involved in the fluoropyrimidine metabolism and resistance mechanisms. We presented emerging preclinical and clinical studies, highlighting the mechanisms by which HDACis can prevent/overcome the resistance and/or enhance the therapeutic efficacy of fluoropyrimidines, potentially reducing their toxicity, and ultimately improving the overall survival of cancer patients. Abstract Although fluoropyrimidines were introduced as anticancer agents over 60 years ago, they are still the backbone of many combination chemotherapy regimens for the treatment of solid cancers. Like other chemotherapeutic agents, the therapeutic efficacy of fluoropyrimidines can be affected by drug resistance and severe toxicities; thus, novel therapeutic approaches are required to potentiate their efficacy and overcome drug resistance. In the last 20 years, the deregulation of epigenetic mechanisms has been shown to contribute to cancer hallmarks. Histone modifications play an important role in directing the transcriptional machinery and therefore represent interesting druggable targets. In this review, we focused on histone deacetylase inhibitors (HDACis) that can increase antitumor efficacy and overcome resistance to fluoropyrimidines by targeting specific genes or proteins. Our preclinical data showed a strong synergistic interaction between HDACi and fluoropyrimidines in different cancer models, but the clinical studies did not seem to confirm these observations. Most likely, the introduction of increasingly complex preclinical models, both in vitro and in vivo, cannot recapitulate human complexity; however, our analysis of clinical studies revealed that most of them were designed without a mechanistic approach and, importantly, without careful patient selection.
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Affiliation(s)
- Laura Grumetti
- Experimetnal Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (L.G.); (R.L.); (F.I.); (B.P.)
| | - Rita Lombardi
- Experimetnal Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (L.G.); (R.L.); (F.I.); (B.P.)
| | - Federica Iannelli
- Experimetnal Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (L.G.); (R.L.); (F.I.); (B.P.)
| | - Biagio Pucci
- Experimetnal Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (L.G.); (R.L.); (F.I.); (B.P.)
| | - Antonio Avallone
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori di Napoli IRCCS “Fondazione Pascale”, 80131 Naples, Italy;
| | - Elena Di Gennaro
- Experimetnal Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (L.G.); (R.L.); (F.I.); (B.P.)
- Correspondence: (E.D.G.); (A.B.); Tel.: +39-081-590-3342 (E.D.G.); +39-081-590-3292 (A.B.)
| | - Alfredo Budillon
- Experimetnal Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (L.G.); (R.L.); (F.I.); (B.P.)
- Correspondence: (E.D.G.); (A.B.); Tel.: +39-081-590-3342 (E.D.G.); +39-081-590-3292 (A.B.)
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13
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Schmulenson E, Zimmermann N, Mikus G, Joerger M, Jaehde U. Current status and future outlooks on therapeutic drug monitoring of fluorouracil. Expert Opin Drug Metab Toxicol 2022; 17:1407-1422. [PMID: 35029518 DOI: 10.1080/17425255.2021.2029403] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION : Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied. AREAS COVERED : This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine. EXPERT OPINION : New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Pre-emptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.
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Affiliation(s)
- Eduard Schmulenson
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Nigina Zimmermann
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Gerd Mikus
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany.,Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.,Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus Joerger
- Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Ulrich Jaehde
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
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14
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Asadi MR, Moslehian MS, Sabaie H, Poornabi M, Ghasemi E, Hassani M, Hussen BM, Taheri M, Rezazadeh M. Stress Granules in the Anti-Cancer Medications Mechanism of Action: A Systematic Scoping Review. Front Oncol 2021; 11:797549. [PMID: 35004322 PMCID: PMC8739770 DOI: 10.3389/fonc.2021.797549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/08/2021] [Indexed: 12/16/2022] Open
Abstract
Stress granule (SG) formation is a well-known cellular mechanism for minimizing stress-related damage and increasing cell survival. In addition to playing a critical role in the stress response, SGs have emerged as critical mediators in human health. It seems logical that SGs play a key role in cancer cell formation, development, and metastasis. Recent studies have shown that many SG components contribute to the anti-cancer medications' responses through tumor-associated signaling pathways and other mechanisms. SG proteins are known for their involvement in the translation process, control of mRNA stability, and capacity to function in both the cytoplasm and nucleus. The current systematic review aimed to include all research on the impact of SGs on the mechanism of action of anti-cancer medications and was conducted using a six-stage methodological framework and the PRISMA guideline. Prior to October 2021, a systematic search of seven databases for eligible articles was performed. Following the review of the publications, the collected data were subjected to quantitative and qualitative analysis. Notably, Bortezomib, Sorafenib, Oxaliplatin, 5-fluorouracil, Cisplatin, and Doxorubicin accounted for the majority of the medications examined in the studies. Overall, this systematic scoping review attempts to demonstrate and give a complete overview of the function of SGs in the mechanism of action of anti-cancer medications by evaluating all research.
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Affiliation(s)
- Mohammad Reza Asadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hani Sabaie
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziye Poornabi
- Student Research Committee, School of Medicine, Shahroud University of Medical Science, Shahroud, Iran
| | - Elham Ghasemi
- Department of Molecular Medicine and Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Mehdi Hassani
- Student Research Committee, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Maryam Rezazadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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Ciaffaglione V, Modica MN, Pittalà V, Romeo G, Salerno L, Intagliata S. Mutual Prodrugs of 5-Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs. ChemMedChem 2021; 16:3496-3512. [PMID: 34415107 PMCID: PMC9290623 DOI: 10.1002/cmdc.202100473] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/18/2021] [Indexed: 12/18/2022]
Abstract
The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the “mutual prodrug” approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad‐spectrum chemotherapeutics available for clinical use today, 5‐fluorouracil (5‐FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5‐FU‐based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.
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Affiliation(s)
- Valeria Ciaffaglione
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy
| | - Maria N Modica
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy
| | - Valeria Pittalà
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy
| | - Giuseppe Romeo
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy
| | - Loredana Salerno
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy
| | - Sebastiano Intagliata
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy
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16
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Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
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Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
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