Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model
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Abstract:
5-Fluorouracil (5-FU) is a standard chemotherapeutic agent to treat solid cancers such as breast, colon, head, and neck. Computational modeling plays an essential role in predicting the outcome of chemotherapy and developing optimal dosing strategies. We developed an integrated mechanistic pharmacokinetics/pharmacodynamics (PK/PD) model examining the influence of 5-FU, as an S-phase specific double-strand break (DSB)-inducing agent, on tumor proliferation. The proposed mechanistic PK/PD model simulates the dynamics of critical intermediate components and provides the accurate tumor response prediction. The integrated model is composed of PK, cellular, and tumor growth inhibition (TGI) sub-models, quantitatively capturing the essential drug-related physiological processes. In the cellular model, thymidylate synthase (TS) inhibition, resultant deoxynucleoside triphosphate (dNTP) pool imbalance, and DSB induction are considered, as well as 5-FU incorporation into RNA and DNA. The amount of 5-FU anabolites and DSBs were modeled to drive the kinetics of the pharmacological tumor response. Model parameters were estimated by fitting to literature data. Our simulation results successfully describe the kinetics of the intermediates regulating the 5-FU cytotoxic events and the pattern of tumor suppression. The comprehensive model simulated the tumor volume change under various dose regimens, and its generalizability was attested by comparing it with literature data. The potential causes of the tumor resistance to 5-FU are also investigated through Monte Carlo analysis. The simulation of various dosage regimens helps quantify the relationship between treatment protocols and chemotherapy potency, which will lead to the development of efficacy optimization.Keywords:
Pharmacodynamics
Thymidine
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Molecular modeling techniques and a knowledge of thymidylate synthase protein structure have assisted in the development of several potent new inhibitors of thymidylate synthase, the enzyme mediating de novo formation of thymidylate for use in DNA synthesis. Information on several new and specific thymidylate synthase inhibitors, including ICI-D1694, 1843U89, AG-331, and AG-337, is presented. The effects of thymidylate synthase inhibition on the induction of thymidylate synthase protein synthesis have raised the question of whether thymidylate synthase inhibition alone will be sufficient to provide a desirable clinical effect. Formation of a thymidylate synthase-inhibitor complex prevents posttranscriptional regulation of thymidylate synthase synthesis, allowing for increased thymidylate synthase synthesis and the possibility of drug resistance. Therefore, recent efforts have also focused on characterizing this increase in thymidylate synthase protein induced by inhibitors of thymidylate synthase and on devising combination drug strategies that may prevent the induction of thymidylate synthase protein synthesis in addition to inhibiting thymidylate synthase activity.
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Iacopetta et al (2001) recently reported on a study investigating colorectal cancer patient survival among patients with different genotypes in the thymidylate synthase promoter region, undergoing either surgery alone or treatment with 5-fluorouracil (5-FU).The authors stated that 'patients with the 3R/3R polymorphism showed no significant long-term survival benefit from chemotherapy (RR=0.62,95% CI 0.30 -1.25, P=0.18) (n=48), whereas those with the 2R/2R or 2R/3R genotype showed significant gains in survival (RR=0.52,95% CI 0.52 -0.82, P=0.005)'.Thus, the authors imply that the 38% survival benefit among patients with the 3R/3R genotype is different from the 48% survival benefit seen among patients with the 2R/2R or 2R/3R genotype.This conclusion is inappropriate: there was no statistical test performed to compare the 38% survival benefit to the 48% survival benefit, and the difference would clearly not be statistically significant.The fact that, in, Table 3, the 3R/3R patients do not show statistically significant survival from surgery alone, whereas the other TS genotypes do, is not the relevant question.
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Pharmacodynamics
ED50
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【Objective】To explore the influence of polymorphism of thymidylate synthetase on the clinical effect of 5-fluorouracil. 【Methods】The genotypes of thymidylate synthetase in 50 untreated esophageal cancer patients were analyzed. The homozygote with twice 28-bp tandem repeated sequence in promoter area was named as S/S,triple 28-bp tandem repeated sequence as R/R,the heterozygote with twice tandem repeated and triple tandem re-peated sequence as R/S. The mRNA level of thymidylate synthetase was detected by RT-PCR. The relationship be-tween the genotype of thymidylate synthetase and clinical effect of 5-fluorouracil was analyzed. 【Results】Among the 50 patients,there were 20 patients of R/R with 5-fluorouracil effect rate of 10%,22 patients of R/S with 5-fluo-rouracil effect rate of 13.6%,8 patients of S/S with 5-fluorouracil effect rate of 50%,the differences of the effect rate among the genotypes of R/R with S/S and R/S with S/S were significant (P 0.05). The mean survival time of the pa-tients of S/S was 20.3 months,which was significantly different from 8.1 months of R/S,and 7.9 months of S/S (P0.05). 【Conclusion】The polymorphism of thymidylate synthetase is a potential factor that may influence the effect of 5-fluorouracil.
Heterozygote advantage
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Objective:This study was designed to characterize the pharmacokinetics and pharmacodynamics of high dose epirubicin in cancer patients Methods:Eleven cancer patients were administered a dose of 100 mg/m 2 epirubicin The concentration of epirubicin in the blood were determined by high performance liquid chromatographic (HPLC)assay The modelling data were performed with a compartment pharmacokinetic modelling program (PCNONLIN) Hematological toxicity was used as the pharmacodynamic index The relationships between the pharmacokinetics and pharmacodynamics and other factors affecting dose modulation were assessed Results: The pharmacokinetics of high dose epirubicin was best described by a typical three compartment model It showed wide interindividual variation There was no correlation between its pharmacokinetics and pharmacodynamics Age was negatively correlated with epirubicin clearance Conclusions: There was no difference for the pharmacokinetic parameters between high dose and low dose Total clearance appears to be decreased with age and indicating that it is necessiary to reduce dose for the elderly patients Tolerance of the patients receiving a dose of 100 mg/m 2 epirubicin was good
Epirubicin
Pharmacodynamics
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Objective
To investigate thymidylate synthase on pemetrexed treatment of lung adenocarcinoma effect relationship.
Methods
The 60 patients with lung adenocarcinoma in our hospital from January 2014 to January 2016 were selected as the research subjects. They were treated with pemetrexed. According to the clinical efficacy, they were divided into the effective group (n=27) and ineffective group (n=33) after 3 courses of treatment. The levels of thymidylate synthase (thymidylate synthase, TS), TS mRNA expression, and the expression of TS protein in the tumor tissues of two groups were analyzed by enzyme-linked immunoadsorbent assay (ELISA), fluorescence quantitative polymerase chain reaction (PCR), and immunohistochemistry. The relationship between TS level and pemetrexed in the treatment of lung adenocarcinoma was investigated.
Results
The level of ST in peripheral blood of the effective group was significantly lower than ineffective group. The objective response rate and protein of ST gene low expression were significantly higher than high expression of ST.
Conclusions
The level of thymidylate synthase in patients with adenocarcinoma of the lung is related to the therapeutic effect of pemetrexed in the treatment of adenocarcinoma of the lung. It can be used as a molecular marker to evaluate the clinical efficacy of pemetrexed in the treatment of patients with lung adenocarcinoma.
Key words:
Thymidylate synthase/ME; Taxoids/TU; Lung neoplasms/DT/ME
Pemetrexed
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B41 Purpose: To identify the good marker for the help of adjuvant 5-fluorouracil (5-FU) therapy to primary colorectal cancer by using different 5-FU regimens. Patients and methods: Primary colorectal cancer tissue from 24 patients were investigated to evaluate the relationship between the mRNA expression level of several 5-fluorouracil (5-FU)-related metabolic enzymes (thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase(TP)) and chemosensitivity to 2 different 5-FU regimens (1. 5-FU concentration 1.0 μg/mL, 24 h exposure 2. 5-FU concentration 0.3 μg/mL, 144 h exposure). Chemosensitivity and mRNA expression levels were measured by using collagen gel droplet embedded culture drug sensitivity tests and real-time quantitative reverse transcription-polymerase chain reaction. Results: The TS mRNA expression level were significantly higher in 5-FU resistant group (T/C > 60%) compared with 5-FU sensitive one (T/C the average, 3.83) were more resistant to both 5-FU regimens than the one with lower TS mRNA (
Dihydropyrimidine dehydrogenase
Thymidine phosphorylase
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Dihydropyrimidine dehydrogenase
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