5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine

Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3–4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II–IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3–4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1–37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3–4 adverse events (OR = 10.40 [95% IC: 1.48–7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3–4 toxicity occurrence (OR = 10.9 [95% IC 1.2–96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity

Sintesis 1-(4-metoksibenzoiloksimetil)-5-fluorourasil sebagai Agen Antikanker

A new compound from 5-fluorouracil (5-FU) derivatives, 1-(4-methoxybenzoyloxymethyl)-5-fluorouracil has been synthesized in a two steps reaction, alkylation (5-FU and formaldehyde to form 1-hydroxymethyl-5-fluorouracil) and esterification (1-hydroxymethyl-5-fluorouracil and 4-methoxybenzoylchloride to form 1-(4-methoxybenzoyloxymethyl)-5-fluorouracil). Reaction product purified by chromatography column, the product has been characteryzed for physical apperance is a yellowish white, crystal and melting range 168-169OC. Based on the FTIR and 1H-NMR spectra, it showed that the purified product does not contain a single compound. This fact is supported by Thin Layer Chromatography (TLC) result showing two spots for the pressure of 1-(4-methoxybenzoyloxymethyl)-5-fluorouracil and 4-methoxybenzoate acid. Keywords: 5-fluorouracil derivates, anticancer, 1-(4-methoxybenzoyloxymethyl)-5-fluorouracil, benzoylation

Total body topical 5-fluorouracil for extensive non-melanoma skin cancer

Background Topical 5-fluorouracil 5% cream is one of the treatment modalities for non-melanoma skin cancer (NMSC). There is a lack of suitable therapies to treat patients with extensive NMSC. In this paper we report two patients with extensive NMSC treated by total body application of topical 5-fluorouracil 5% cream. Observations Topical 5-fluorouracil 5% cream was applied twice daily to the total body, including normal appearing skin. During the treatment, weekly blood samples were taken for measurement of 5-fluorouracil levels. All samples showed a 5-fluorouracil level less than the detection level of 10 mu g/l. Total body 5-fluorouracil 5% cream was shown to be an effective treatment in our patients; the majority of lesions cleared in both patients. Conclusions In conclusion, total body topical 5-fluorouracil 5% cream application was successful in two patients with extensive NMSC. No detectable serum level of 5-fluorouracil could be determined. Pain and secondary infections were important side effects in our patients. However, in patients with extensive NMSC this treatment may be considered

Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study

Purpose: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis. Experimental design: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days. Results: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime. Conclusion: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies

DPYD and fluorouracil-based chemotherapy: Mini review and case report

5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas

Studi Aktivitas Antioksidan Senyawa 1-(p-klorobenzoiloksimetil)-5-fluorourasil dengan Metode Molecular Docking dan Metode DPPH (Antioxidant Activity of 1-(p-chlorobenzoyloxymethyl)-5-Fluorouracyl Using Molecular Docking and DPPH Method)

Cellular damage caused by reactive oxygen species (ROS) free radical and antioxidant activity has an important role as free radical scavenging in body. This study was carried out to evaluate in vitro antioxidant and ligand afinity toward human ROS receptor (PDB code: 3ZBF). In DPPH method, 1-(p-chlorobenzoyloxymethyl)-5-fluorouracil dissolved in etil acetat, while 5-fluorouracil and ascorbic acid as standard dissolved in methanol. The free radical scavenging activity was measured spectrometrically with maximum wavelength at 512 nm. DPPH method show that ascorbic acid have strong antioxidant activity (IC50 = 19.092 ppm), while 1-(p-chlorobenzoyloxymethyl)-5-fluorouracil (IC50 = -2,500,245 ppm) and 5-fluorouracil (IC50 = -4,998 ppm) have not antioxidant activity. Molecular docking (in silico) toward human ROS receptor was indicate 1-(p-chlorobenzoyloxymethyl)-5-fluorouracil (Ki = -6.2 ± 0.04 kkal/mol) has best activity than ascorbic acid (Ki = -4.8 ± 0.19 kkal/mol) and 5-fluorouracil (Ki = -4.6 ± kkal/mol).   Keywords: 1-(p-chlorobenzoyloksimethyl)-5-fluorouracil, 5-Fluorouracyl, antioxidants, DPPH, molecular dockin

Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m−2 plus 5-fluorouracil 425 mg m−2. Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve0→3h in the index patient was 24.1 mg h l−1 compared to 9.8±3.6 (range 5.4–15.3) mg h l−1 in control patients. The 5-fluorouracil clearance was 520 ml min−1 vs 1293±302 (range 980–1780) ml min−1 in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h−1) compared to the six controls (10.3±1.6, range 8.0–11.7 nmol mg h−1). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVS14+1G>A point mutation. Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity

Enhancing anticancer cytotoxicity through bimodal drug delivery from ultrasmall Zr MOF nanoparticles

Dual delivery of dichloroacetate and 5-fluorouracil from Zr MOFs into cancer cells is found to enhance in vitro cytotoxicity. Tuning particle size and, more significantly, surface chemistry, further improves cytotoxicity by promoting caveolae-mediated endocytosis and cytosolic cargo delivery

The Effect of 5-Fu and Ruxolitinib on Mitochondrial Apoptosis in Glioblastoma U87 Cell Line

DergiPark: 819208tmsjAims: The aim of this study is to carry out the effect of 5-Fluorouracil alone or combined with Ruxolitinib on both apoptosis and JAK/STAT pathway in U87 glioblastoma cells. Methods: We used U87 glioblastoma cell lines as the human brain cancer cells. We treated the cells with 5-Fluorouracil (3.125 ?M-400 ?M) alone and with a combination of Ruxolitinib (100 ?M or 400 ?M of Ruxolitinib with 3.125-25 ?M 5-Fluorouracil), and performed the MTT test for calculating IC50 value. Molecular fluorescence staining was performed with Hoechst and acridine orange/ethidium bromide probes. The alteration in mitochondrial apoptosis and JAK/STAT pathways to drug treatment was analyzed by the qRT-PCR assay. Results: Decrease in cell viability was more prominent in U87 cells treated with a combination of 5-Fluorouracil and Ruxolitinib compared to those treated with 5-Fluoro- uracil alone. In gene expression analysis, apoptosis signals were observed in cells treated with 5-Fluorouracil alone and 5-Fluo- rouracil+Ruxolitinib treatment. Conclusion: Treatment with 5-Fluorouracil alone and 5-Fluorouracil+Ruxolitinib combination increased apoptosis in U87 glioblastoma cells. However, it is difficult to mention an evident difference between treatments. Therefore, further studies are needed