Deciphering the potential value of 5-fluorouracil metabolic enzymes in predicting prognosis and treatment response of colorectal cancer patients

Gajjar, Kinjal; Vora, Hemangini H.; Kobawala, Toral P; Trivedi, Trupti; Ghosh, Nandita

doi:10.1177/1724600817748539

Cited by 8 publications

(10 citation statements)

References 36 publications

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“…Even so, its direct correlation in 5-FU treatment outcome was previously a subject of debate as certain studies linking elevated expression with worse patient prognosis [ 242 , 243 , 244 ]. Recent studies later conclusively determined that TYMP overexpression may only benefit early-stage patients in prolonging time to disease progression, relapse-free survival, and OS [ 229 , 230 , 231 , 232 , 233 , 245 ]. This is supported by experimental studies in which enhanced 5-FU cytotoxicity is observed in conditions where TYMP is upregulated in colon cancer cells and xenograft mice [ 234 , 246 ].…”

Section: Mechanism Of Resistance By Key 5-fluorouracil Enzymesmentioning

confidence: 99%

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Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

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Section: Mechanism Of Resistance By Key 5-fluorouracil Enzymesmentioning

confidence: 99%

“…•Meta-analysis: poor patients' prognosis when TYMP is suppressed[229].•Increase disease recurrence in patients with TYMP underexpression[230].•Low TYMP expression is associated with reduced patients' relapse-free survival (RFS)[231].•Low TYMP is associated with poor patient outcome[232].…”

mentioning

confidence: 99%

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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Section: Discussionmentioning

confidence: 99%

“…A few Indian studies have explored the association of DPYD variants with 5‐FU/capecitabine‐mediated toxicity 11–16,24 . Low DPYD expression was linked to unfavourable overall survival in colorectal cancer patients 24 . DPYD*9A (rs1801265) variant was found to increase the risk for the hand‐foot syndrome, diarrhea and thrombocytopenia following treatment with capecitabine and oxaliplatin in colorectal cancer 11 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic profiling of dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population

Naushad¹,

Hussain

Alrokayan

et al. 2020

The Journal of Gene Medicine

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BackgroundThe present study aimed to delineate the pharmacologically relevant dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population.MethodsWe screened 2000 Indian subjects for DPYD variants using the Infinium Global Screening Array (GSA) (Illumina Inc., San Diego, CA, USA).ResultsThe GSA analysis identified seven coding, two intronic and three synonymous DPYD variants. Level 1A alleles (rs75017182, rs3918290, P633Qfs*5 and D949V) were found to be rare (minor allele frequency: 1.889%), whereas Level 3 alleles were observed to be predominant (C29R: 24.91%, I543V: 9.047%, M166V: 8.993% and V732I: 8.44%). In silico predictions revealed that all Level 1A alleles were deleterious, whereas three (M166V, S534N and V732I) of seven Level 3 alleles were damaging. CUPSAT analysis revealed that two Level 1A (P633Qfs*, D949V) and three Level 3 (I543V, V732I and S534N) variants were thermolabile. The pooled Indian data showed that V732I, S534N and rs3918290 variants were associated with 5‐FU/capecitabine toxicity, whereas C29R, I543V and M166V variants exhibited the null association. A comparison of our data with other population data from the ‘Allele Frequency Aggregator’ (https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/) database showed similarities with the South Asian data.ConclusionsWe have identified four Level 1A (non‐functional/dysfunctional) and seven Level 3 variants in the DPYD gene. The pooled Indian data revealed the association of V732I, S534N and rs3918290 variants with 5‐FU/capecitabine toxicity. Clustering analysis revealed the similarities in the DPYD profiles of the Indian and South Asian populations.

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“…In recent years, there have been many therapeutic drugs for colorectal cancer. Fluorouracil drugs represented by 5-Fu are the cornerstone of colorectal cancer chemotherapy (Gajjar et al, 2018). During the treatment of recurrent tumors, stubborn tumor cells will produce chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest

Zhang

Pan

et al. 2020

Front. Bioeng. Biotechnol.

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Objective: Colorectal cancer is a malignant tumor of the digestive system with high morbidity and mortality. 5-fluorouracil remains a widely used chemotherapeutic drug in the treatment of advanced colorectal cancer, but chemotherapy drugs are prone to develop drug resistance, p53 deletion or mutation is an important reason for the resistance of colorectal cancer cells to 5-fluorouracil. β-elemene has been proved to have the potential of reverse chemotherapy drug resistance, but the mechanism is unknown. This study aimed to investigate the effect of β-elemene to 5-fluorouracil in drug-resistant p53-deficient colorectal cancer cells HCT116p53 −/− , and determine the possible molecular mechanism of β-elemene to reverse 5-fluorouracil resistance. Methods: The effect of β-elemene on HCT116p53 −/− cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. The autophagy was detected by western blot, immunofluorescence and transmission electron microscope. Determine the role of Cyclin-related protein Cyclin D3 in β-elemene reversing the resistance of HCT116p53 −/− to 5-fluorouracil was detected by overexpression of Cyclin D3. The effect of β-elemene on the tumorigenic ability of p53-deficient colorectal cancer cells was detected establishing HCT116p53 −/− all line xenograft model. Results: For p53 wildtype colorectal cancer cells, β-elemene could augment the sensitivity of 5-fluorouracil, for p53-deficient colorectal cancer cells, β-elemene significantly inhibited cell proliferation in a concentration-dependent manner, and

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Deciphering the potential value of 5-fluorouracil metabolic enzymes in predicting prognosis and treatment response of colorectal cancer patients

Abstract: The above findings suggest that coexpression of 5-FU metabolic enzymes possess significant prognostic value and could be useful biomarkers in colorectal cancer patients.

Cited by 8 publications

References 36 publications

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Pharmacogenetic profiling of dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population

β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest

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