Predictive diagnostics in colorectal cancer: impact of genetic polymorphisms on individual outcomes and treatment with fluoropyrimidine-based chemotherapy

Abstract

The 5-fluorouracil (5-FU)-based chemotherapy is a standard treatment for patients with colorectal cancer. However, a relevant number of patients suffer from severe toxic side effects, such as haemotoxicity, while lacking clinical response to adjuvant therapy. The inter-individual variations of drug toxicity and efficacy of the pyrimidine antagonist observed in clinical practice are mainly determined by genetic polymorphisms. The screening of genotypes, such as thymidylate synthase, dihydropyrimidine dehydrogenase, methylene tetrahydrofolate reductase, orotate phosphoribosyltransferase or glutathione S-transferase, could help identifying those patients with colorectal carcinoma who can actually benefit from a 5-FU-based therapy. The current chapter elucidates the roles of the polymorphisms in the enzymes involved in the 5-FU metabolic pathway as prognostic and predictive markers. It reports on the relationship between various genotypes in patients with colorectal carcinoma and their responsiveness to a 5-FU-based chemotherapy, and concludes with an outlook on possible future directions in treatment of colorectal cancer.

Enhancing Prostate and Bladder Cancer Treatment: Exploring the Synergistic Potential of Entecavir and 5-Fluorouracil Combinations

“…However, the software's prediction accuracy for these enzymes (below 50%) raises questions about their involvement in the 5-FU metabolism. In fact, 5-FU is primarily metabolized by enzymes involved in nucleotide metabolism, contributing to its anticancer effects [43]. Moreover, a study conducted by Park et al [44], showing little or no inhibitory effect of 5-FU on CYP enzymes, stated that DDIs between the co-administered drugs and 5-FU are not related to CYP inhibition.…”

TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients

“…The thymidylate synthase (TYMS) gene is a prospective marker of clinical response and toxicity to 5-FU since this enzyme is a molecular target of fluoropyirimidines [18,19], and polymorphisms in the regulatory regions of the TYMS gene may affect its level of expression [20,21]. However, a number of studies contain conflicting results that do not allow proper evaluation the clinical value of these allele variants [22][23][24]. Particularly, some studies report significant association between the clinical response and/or AEs and variations in the TYMS 5 UTR and 3 UTR regulatory regions, while other studies contain contradictory results [25][26][27][28].…”

Cancer diagnostics and treatment: are we ready to implement PPPM?

“…chemotherapy is the focus of a review of colorectal cancer patients [10]. Genetic polymorphisms are important for those patients who undergo fluoropyrimidine chemotherapy in terms of inter-individual variations of drug toxicity, tolerability, and efficacy.…”