5-FU | Close connection between drug testing and genetic testing
发布日期：
2024-03-25
浏览次数：
0

Current status of 5-fluorouracil (5-FU) drug testing


5-Fluorouracil (5-FU) is widely used in the treatment of solid malignancies, being the backbone cytotoxic prescribed in gastrointestinal cancers [1]. Despite some advances in its management, 10–30% of patients treated with fluoropyrimidines as a monotherapy experience severe treatment-related toxicity leading to death in 0.5–1% of patients [1].


The most well-known cause of 5-FU intolerance is deficiency of dihydropyrimidine dehydrogenase (DPD) activity—the key enzyme responsible for its metabolism, which has a high mutation rate in the population. Complete DPD deficiency is somehow rare and observed in only 0.1 to 0.5% of the population, whereas partial DPD deficiency is observed in 3 to 15% of the population [2]. Current clinical practice often recommends that for patients with moderate or partial DPD enzyme activity (uracil concentration between 16-150 ng/ml), it is recommended that the initial dose be reduced by at least 50%, while for patients with complete DPD deficiency (uracil concentration >150 ng/ml), it is strongly recommended to choose alternative drugs [3].

DPD converts uracil, its endogenous substrate, into dihydrouracil, and the pretreatment dihydrouracilemia (UH2)/uracilemia (U) ratio or uracil concentrations (U) alone have the great potential to identify patients at risk of severe fluoropyrimidine-associated toxicity. According to certain studies, the UH2/U ratio correlates with 5-FU clearance and risk of toxicity; however, despite strong evidence on its clinical validity, the use of theUH2/U ratio in daily clinical practice is still limited.







Dosing based solely on DPD activity and genotype may result in insufficient 5-FU exposure.



Although over-exposure is an important concern for oncologists, several papers have shown that almost 50% of patients treated with 5-FU are at risk of under-exposure, leading to sub-optimal efficacy [4]. Therefore, 5-FU therapeutic drug monitoring (TDM) has been suggested as an option to ensure a correct exposition in all patients. The research team conducted a retrospective study to determine whether the high proportion of underexposure to 5-FU was related to the current requirements for DPD deficiency testing.
In the study by Marine Dolat et al., a total of 169 patients (80 females and 89 males) were included in our study. Their median age was 68 (range of 40–88) years. The main primary tumor sites were colorectal (40.8%), pancreas (31.4%), and stomach (11.2%), and were mostly metastatic (76.3%). 5-FU concentrations were sampled over one cycle of chemotherapy for 56 patients, two cycles for 54 patients, three cycles for 34 patients, four cycles for 17 patients, and five or more for 8 patients. In the study, data analysis was performed on patients' U, UH2/U ratio, genotype characteristics, and 5-FU metabolism.
The results of this trial showed that there is no close relationship between patient U value or UH2/U ratio and DPYD genotype, which is in sharp contrast to existing papers. It was also pointed out for the first time that there was also a lack of correlation between the 5-FU clearance rate and DPYD genotype obtained in this study.
However, the most important finding of this study is that there was no relationship between the patient's U value or UH2/U ratio and 5-FU clearance when the U value or UH2/U ratio was between 3-37.6 ng/mL and 3-21.6. However, this conclusion cannot deny the previous research conclusion that the two are related, because the highest U value of the study subjects in this trial was only 37.6 ng/ml, and there were a large number of patient groups above 40 ng/ml in previous studies. The study missed those extreme patients. However, patients in this study with U values greater than 30 ng/mL should have their 5-FU use adjusted in accordance with medical recommendations. However, these patients actually face a higher risk of underexposure, according to the study's results. Their treatment ultimately benefited from the application of 5-FU TDM, which ensured its normal blood concentration. In addition, 45% of patients with U≥16 ng/mL also benefited from timely dose increases in the first two treatment cycles after detecting low AUC.
Although the number of cases in this study is insufficient and there is a lack of patients with high U values, the actual treatment process shows that if you simply follow the recommendation to reduce the dose of U≥16 ng/mL, patients are at risk of underexposure, and 5-FU TDM should be performed to avoid loss of efficacy.


Diagreat fully automatic chemiluminescence 5-fluorouracil drug concentration monitoring solution

Diagreat Biotech's TDM-5-fluorouracil detection kit uses chemiluminescence immunoassay method and is equipped with a fully automatic chemiluminescence immunoassay analyzer to truly meet the "fast, accurate and simple" clinical testing needs, providing solutions for individualized treatment and precise medication for patients.
Beijing Diagreat Biotechnologies Co, Ltd. has always insisted on in-depth scientific research, focusing on innovation, and continuously harvested invention patents.
At present, Diagreat Biotech’s anti-tumor drug testing items include: paclitaxel, 5-fluorouracil, methotrexate, etc., and a steady stream of items will be launched in the future to meet the needs of clinical testing.


5-FU | Close connection between drug testing and genetic testing



References:

1. Tsalic, M., et al., Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients. Am J Clin Oncol, 2003. 26(1): p. 103-6.

2. Launay, M., et al., Upfront Dpd Deficiency Detection to Secure 5-Fu Administration: Part 2- Application to Head-and-Neck Cancer Patients. Clin Cancer Drugs, 2017. 4(2): p. 122-128.

3. Caudle, K.E., et al., Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther, 2013. 94(6): p. 640-5.

4. Macaire, P., et al., Therapeutic drug monitoring as a tool to optimize 5-FU-based chemotherapy in gastrointestinal cancer patients older than 75 years. Eur J Cancer, 2019. 111: p. 116-125.



Last：POCT featured products assisting in diagnosis of heart failureNext：New CLIA product | Immunoglobulin E shines on the market

Related Recommendations