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The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys 27 Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys 27 Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys 27 Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P =0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P =0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys 27 Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

This study evaluates by comet assay the induction of early DNA damage in healthcare workers of an oncology hospital regularly handling antineoplastic drug mixtures. The aim was to identify a suitable biomarker of DNA damage by exposure to low levels of such drugs. We studied 12 day hospital nurses and 13 oncology ward nurses who performed up to 300 and up to 35 drug administrations per week, respectively, and five pharmacy employees who regularly prepared mixtures of antineoplastic agents. Thirty healthy subjects were selected as controls. For exposure evaluation, we performed environmental monitoring of 5-fluorouracil, cytarabine, gemcitabine, cyclophosphamide, and ifosfamide in selected work areas of pharmacy and day hospital units and biological monitoring of urine for the 5-fluorouracile metabolite, alpha-fluoro-beta-alanine. We evaluated early DNA damage in lymphocytes and exfoliated buccal cells by comet assay measuring tail moment (TM) parameter that indirectly indicates the presence of DNA damage. Environmental monitoring detected cyclophosphamide, 5-fluorouracil and ifosfamide, with higher levels of contamination in day hospital unit. The biological monitoring measured detectable levels of alpha-fluoro-beta-alanine only in three nurses. Comet assay showed an increase on exfoliated buccal cells, even if not statistically significant, of mean TM with respect to controls in day hospital nurses (43.2 vs. 28.6, respectively) while ward nurses and pharmacy technicians did not show differences. Comet assay performed on lymphocytes did not show appreciable differences between exposed and controls. The employment of the sensitive comet assay, which is able to detect early the effects of a recent exposure to genotoxic substances, allowed us to find a slight DNA damage, only on exfoliated buccal cells of day hospital nurses, the group handling the highest amount of drugs during the administration process. This finding suggests that comet assay on exfoliated buccal cells could represent a useful tool to evaluate early and still repairable genotoxic effects of exposure to antineoplastic drug mixtures and then contribute to the improvement of the hospital safety practices.

5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development.

Immunotherapy is one of the key strategies for cancer treatment. The cGAS-cGAMP-STING-IRF3 pathway of cytosolic DNA sensing plays a pivotal role in antiviral defense. We report that the STING activator cGAMP possesses significant antitumor activity in mice by triggering the STING-dependent pathway directly. cGAMP enhances innate immune responses by inducing production of cytokines such as interferon-β, interferon-γ and stimulating dendritic cells activation, which induces the cross-priming of CD8 + T cells. The antitumor mechanism of cGAMP was verified by STING and IRF3, which were up-regulated upon cGAMP treatment. STING-deficiency dramatically reduced the antitumor effect of cGAMP. Furthermore, cGAMP improved the antitumor activity of 5-FU and clearly reduced the toxicity of 5-FU. These results demonstrated that cGAMP is a novel antitumor agent and has potential applications in cancer immunotherapy.

Recently, therapeutic drug monitoring of 5-fluorouracil (5-FU), the key chemotherapeutic drug for colorectal cancer, has been applied in daily clinical practice and has contributed towards improving clinical outcomes. However, current dose modifications are based only on values of the area under the plasma concentration-time profile, which are simply calculated from plasma 5-FU concentrations and infusion periods. When dose-limiting toxicities occur, the dosing is empirically reduced or discontinued, leading to treatment failure. To prevent this predictable failure and obtain better clinical outcomes, rational dosage-based strategies are required for 5-FU. Combining therapeutic drug monitoring with a mathematical approach using a pharmacokinetic- pharmacodynamic/toxicodynamic model is expected to help simulate time-course profiles of the efficacy of drugs and the degree of toxicity, thereby contributing towards dose setting for individual patients. Therefore, to facilitate pharmacometric modelling and simulation techniques for optimising current oncology therapies, this review focuses on pharmacometrics approaches for personalizing 5-FU-based chemotherapy.

5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent that is extensively utilized in the management of malignancies; however, its clinical utility is constrained by its narrow therapeutic index and dose-limiting toxicities. The study aimed to study the hepato-nephroprotective effects of epigallocatechin gallate (EGCG) and EGCG mediated selenium nanoparticles and their effect in mitigating the toxicity induced by 5-FU. EGCG-functionalized selenium nanoparticles (EGCG-SeNPs) were produced by mixing sodium selenite, with EGCG acting as both the reducing and stabilizing agent. Nanoparticles were characterized using UV-vis spectroscopy, FT-IR, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. 35 adult rats were randomly assigned to control, 5-FU, 5-FU + Na SeO , 5-FU + EGCG, and 5-FU + EGCG-SeNPs groups. Hepatorenal toxicity was induced by intraperitoneal 5-FU administration during the final five days of the experiment. Serum biochemical markers, tissue oxidative stress, antioxidant enzyme, inflammatory cytokine levels, and apoptosis-related gene expression were evaluated. Immunohistochemical analysis of Nrf2 and Keap1 and histopathological examination of tissues were performed. 5-FU induced severe hepatorenal toxicity, evidenced by marked elevations in liver and kidney function biomarkers, excessive oxidative stress, inflammatory cytokine overproduction, NF-κB activation, and apoptotic signaling. Treatment with EGCG-SeNPs markedly ameliorated 5-FU-induced hepatic and renal dysfunction, restoring liver enzyme and kidney biomarker levels to near-normal levels more effectively than EGCG or sodium selenite alone. EGCG-SeNPs significantly suppressed lipid peroxidation, NGAL, and inflammatory mediators while robustly enhancing antioxidant defenses and activating the Nrf2/HO-1 pathway with concomitant Keap-1 downregulation, strongly inhibited NF-κB signaling, normalized cytokine balance, reduced poly (ADP-ribose) (PAR) activation, and attenuated apoptosis. EGCG-SeNPs confer superior protection against 5-FU-induced hepatorenal toxicity compared to EGCG or inorganic selenium alone. The potent protective effects of EGCG-SeNPs are mediated through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, primarily via activation of the Nrf2/HO-1 axis and suppression of NF-κB signaling.

Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50-60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. (246 words in abstract).

Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus and has a significant clinical and economic impact. Although oral and intestinal mucositis can occur concurrently in the same individual, these conditions are often studied independently using organ-specific models that do not mimic human disease. Hence, the purpose of this scoping review was to provide a comprehensive yet systematic overview of the animal models that are utilised in the study of chemotherapy-induced mucositis. A search of PubMed/MEDLINE and Scopus databases was conducted to identify all relevant studies. Multiple phases of filtering were conducted, including deduplication, title/abstract screening, full-text screening, and data extraction. Studies were reported according to the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. An inter-rater reliability test was conducted using Cohen’s Kappa score. After title, abstract, and full-text screening, 251 articles met the inclusion criteria. Seven articles investigated both chemotherapy-induced intestinal and oral mucositis, 198 articles investigated chemotherapy-induced intestinal mucositis, and 46 studies investigated chemotherapy-induced oral mucositis. Among a total of 205 articles on chemotherapy-induced intestinal mucositis, 103 utilised 5-fluorouracil, 34 irinotecan, 16 platinum-based drugs, 33 methotrexate, and 32 other chemotherapeutic agents. Thirteen articles reported the use of a combination of 5-fluorouracil, irinotecan, platinum-based drugs, or methotrexate to induce intestinal mucositis. Among a total of 53 articles on chemotherapy-induced oral mucositis, 50 utilised 5-fluorouracil, 2 irinotecan, 2 methotrexate, 1 topotecan and 1 with other chemotherapeutic drugs. Three articles used a combination of these drugs to induce oral mucositis. Various animal models such as mice, rats, hamsters, piglets, rabbits, and zebrafish were used. The chemotherapeutic agents were introduced at various dosages via three routes of administration. Animals were mainly mice and rats. Unlike intestinal mucositis, most oral mucositis models combined mechanical or chemical irritation with chemotherapy. In conclusion, this extensive assessment of the literature revealed that there was a large variation among studies that reproduce oral and intestinal mucositis in animals. To assist with the design of a suitable preclinical model of chemotherapy-induced alimentary tract mucositis, animal types, routes of administration, dosages, and types of drugs were reported in this study. Further research is required to define an optimal protocol that improves the translatability of findings to humans.

FOLFOX, a commonly prescribed chemotherapeutic regimen, associated with significant neurotoxicity, that necessitates stop administration in some cases, hence, this study aimed to investigate the molecular mechanisms underlying FOLFOX-induced neurotoxicity in the brain and sciatic nerve, and determining its cerebral concentration via HPLC technique. 48 rats were divided into four groups: normal control, Oxaliplatin (6 mg/kg), 5-Fluorouracil (50 mg/kg), and a combination group (oxaliplatin 6 mg/kg + 5-fluorouracil 50 mg/kg). Behavioral tests in addition to samples collection from cerebral tissues, sciatic nerves, and blood were conducted. Tissue histological and biochemical changes were determined, including oxidative stress markers (Nrf2, SOD2, HO-1), apoptotic proteins (Bax, cCaspase-3, Bcl-2), and inflammatory biomarkers (COX-II, TNF-α, IL-6, NF-κβ). A new HPLC method was developed and validated to quantify oxaliplatin and 5-fluorouracil (5-Flu) concentrations in the brain tissue. Both oxaliplatin and 5-Flu induced a substantial oxidative stress, evidenced by reduced expression of Nrf2, SOD2, and HO-1 proteins, associated with a significant upregulation of the pro-apoptotic proteins Bax and cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Inflammatory markers were increased in all treated groups, and the highest levels were observed in the combination group. HPLC analysis confirmed a significantly higher concentration of both drugs in the cerebral tissue of the combination group. Histopathological findings revealed neuronal damage and inflammation associated by increased Glial fibrillary acidic protein (GFAP) and decreased neural cell adhesion molecule (NCAM) expression. Behavioral assessments demonstrated markedly reduced pain thresholds in treated animals. This study identified a novel mechanisms underlying FOLFOX neurotoxicity involving activation of the pro-apoptotic BAX/cCaspase-3 pathway and suppression of the Nrf2/KEAP-1/SOD2/HO-1 antioxidant defense mechanism. These disorders induced a neuronal injury, evidenced by altered GFAP and NCAM expression. The findings highlight the synergistic role of FOLFOX components in driving oxidative stress, apoptosis, and inflammation, collectively contributing to neurotoxicity.

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent whose incorporation into nucleic acid plays an essential role in its therapeutic efficacy. 5-FU induces severe reproductive toxicity, which has been shown to be reversible. However, the underlying mechanisms have not been fully elucidated. Since single-strand-selective monofunctional uracil-DNA glycosylase 1 (Smug1) is a key enzyme in the excision of 5-FU, we investigated its potential role in the reversible reproductive toxicity of 5-FU by integrating knockdown, overexpression and LC‒MS/MS approaches. 5-FU treatment increased Smug1 and Dkc1 expression but blocked rRNA maturation in preimplantation embryos. Smug1 knockdown inhibited Dkc1 expression and impaired rRNA maturation, leading to reduced preimplantation embryo development. In contrast, Smug1 overexpression alleviated the inhibitory effects of 5-FU on rRNA and oocyte maturation and partially rescued 5-FU-induced developmental defects in preimplantation embryos. LC‒MS/MS analysis further revealed that overexpression of Smug1 reduced the levels of RNA incorporated 5-FUrd, the metabolite of 5-FU, indicating that Smug1 potentially alleviates reproductive toxicity by excising 5-FU from RNA. Our findings revealed the active involvement of Smug1 in counteracting 5-FU-induced reproductive toxicity and provide valuable references for the development of new strategies to reduce the adverse effects of 5-FU.