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Background: Colorectal cancer (CRC) is the deadliest malignancy in the world. The first-line chemotherapy used for CRC is 5-fluorouracil (5-FU). 5-FU completely eradicates rapidly proliferating and terminally differentiated tumor cells but fails to target cancer stem cells (CSCs). As a result, the tumor may shrink temporarily, but remnant CSC multiplies and forms a tumor again more aggressively. The recurrence and resistance lead to metastasis., Methodology: CRC was induced in 12 Sprague-Dawley (RPCP/IAEC/2019-20/R2) rats by 1,2 dimethyl hydrazine. Later, animals were treated with 5-FU for 7 weeks at a 10 mg/kg dose by the subcutaneous route. At the end of treatment, half population was sacrificed (6), whereas the remaining half (6) was left without treatment of 5-FU for 5 weeks and then sacrificed. Parameters such as body weight, complete blood count (CBC), immune cell subset (CD4, CD8, and NK cells), colon length to weight index, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level, occult blood in stool, tumor multiplicity, and liver metastasis were estimated. In addition, the dissected colon was fixed in formalin and sent to the histology lab for hematoxylin-eosin staining and immunohistochemistry at both intervals., Results: All blood and tissue-based markers have shown significant differences (p < 0.05) between the animals sacrificed at the end of the 27th week and the end of the 32nd week for 5-FU treatment., Conclusion: It can be concluded that 5-FU up-regulates inflammatory cytokines and cell surface markers of CSC that promote CRC stemness via the Wnt/β-catenin pathway. Also, involvement of Nf-κB, fibronectin, MMP-9, and RANKL leads to tumorigenesis, disease aggressiveness, metastasis, and resistance., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Background: Genomic polymorphisms of DNA repair enzymes-excision repair cross complementation group 1 (ERCC1), excision repair cross complementation group 2 (ERCC2), and X-ray repair cross complementation group 1 (XRCC1) correlate with survival and therapeutic responses in colorectal cancer (CRC) patients. Therefore, the present study examined the frequency of ERCC1 C118T, ERCC2 Lys751Gln, and XRCC1 Arg399Gln polymorphisms and their prognostic and predictive values in CRC patients. Method: In this retrospective study, a total of 143 CRC patients were evaluated for these polymorphisms by PCR-RFLP. Results: The majority of the patients showed heterozygous C/T (56%) compared to wild type C/C (29%) and variant T/T (15%) genotypes for ERCC1 C118T polymorphism. ERCC2 Lys751Gln polymorphism showed wild type A/A (44%), heterozygous A/C (40%), and variant C/C genotypes (16%). The frequency of XRCC1 Arg399Gln polymorphism was 48% (wild type G/G), 42% (heterozygous G/A), and 10% (variant A/A). The relapse-free survival (RFS) significantly decreased in patients with ERCC1 118 C/C wild type genotype in the subgroups of patients with advanced stage and colon cancer; however, variant T/T genotype correlated with reduced overall survival (OS) in patients treated with combined drug 5-FU/Oxaliplatin. Taken together, in CRC patients and patients treated with 5-FU/Oxaliplatin, ERCC2 Lys751Gln A/A wild type genotype led to significantly unfavorable clinical outcomes. However, XRCC1 Arg399Gln polymorphism did not show any significant association with prognosis. Additionally, on analyzing combined effect of ERCC1 and ERCC2 polymorphisms, a significant reduced OS in patients with both unfavorable genotypes (ERCC1: C/C and ERCC2: A/A) was found. Furthermore, in the subgroup of patients treated with 5-FU/Oxaliplatin, RFS and OS significantly decreased in patients with both unfavorable genotypes (ERCC1: T/T and ERCC2: A/A). Conclusion: The significant relationship of ERCC1 C118T and ERCC2 Lys751Gln polymorphisms with prognosis and treatment response reflects the vital role of these molecules as prognostic and predictive markers in patients with CRC. Additionally, the combined evaluation of ERCC1 and ERCC2 polymorphisms might identify high risk CRC patients with poor prognosis. [ABSTRACT FROM AUTHOR]