Development and clinical validation of a simple and fast UPLC-ESI-MS/MS method for simultaneous quantification of nine kinase inhibitors and two antiandrogen drugs in human plasma: Interest for their therapeutic drug monitoring

et al. 2022

Gastric Cancer

Background Imatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1–3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites. Methods This study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism. Results The results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance. Conclusions Our findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs. Graphical abstract The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells. Supplementary Information The online version contains supplementary material available at 10.1007/s10120-022-01332-7.

Section: Introductionmentioning

confidence: 99%

SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib

Chen

et al. 2022

Gastric Cancer

“…So far, several methods have been proposed for the determination of RUX in plasma or serum. [17][18][19][20][21] However, these methods either involve complicated sample preparation that is not suitable for rapid clinical testing or have a narrow detection range that is not suitable for pediatric clinical applications. In this study, a sensitive and convenient liquid chromatography tandem mass spectrometry (LC-MS/MS) method to determine the plasma concentration of RUX was developed and validated.…”

Section: Introductionmentioning

confidence: 99%

“…18 Most importantly, the sample amount of this method was only 50 mL while the quantitative linearity range was satisfactory, which is more suitable for pediatric patients from the perspective of protecting children as well as sensitivity compared to previous methods. [17][18][19]21 In addition, pharmacokinetic studies have found that high-fat and high-calorie diets will affect the bioavailability of RUX. 22 Therefore, it is necessary to verify the interference of lipemic samples on detection.…”

Section: Introductionmentioning

confidence: 99%

Development and application of an LC-MS/MS method for pharmacokinetic study of ruxolitinib in children with hemophagocytic lymphohistiocytosis

Sun

et al. 2022

Anal. Methods

“…As an oral small-molecule targeted drug, IM has huge intra-individual differences (about 75%) and inter-individual differences (60%) [13], and it was pointed out that the determination of plasma drug concentration of IM is of great clinical signi cance for patients with metastatic, relapsed and unresectable GIST in the National Comprehensive Cancer Network on the Diagnosis and Treatment of GISTs (NCCN, 2020 edition) [14]. Plasma drug concentration refers to the drug concentration in plasma, including free drug concentration and drug concentration bound to plasma protein [15].…”

Section: Introductionmentioning

confidence: 99%

Sensitive Metabolites and Single Nuclear Polymorphisms of OCT1 on Imatinib Meyslate in Patients with Gastrointestinal Stromal Tumors (GISTs)

Chen

Jia

et al. 2021

Preprint

Imatinib mesylate (IM) is highly efficacious in the treatment of gastrointestinal stromal tumors (GISTs). Therapeutic drug monitoring (TDM) and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to explore the most sensitive metabolites and the role of organic cation transporter 1 (OCT1) on single nuclear polymorphisms (SNP) of IM treatment, which could supply a greater mechanistic understanding of therapeutic effect or resistance of IM. A total of 40 human serum samples from patients with GISTs were collected for TDM. Basing on the results of TDM, the untargeted metabolomic analysis was to determine characteristics of the serum. Principal component analysis (PCA), orthogonal partial least-squares discrimination analysis (OPLS-DA), and heat map were used for multivariate analysis. In addition, KEGG database were used to identify the pathways of metabolites. Differential metabolites were identified based on a heat map with a t-test threshold (p < 0.05), fold-change (FC) threshold (FC > 1.5 or FC < 2/3) and variable importance (VIP) in the projection (VIP>1). The potential differential metabolites were included D-sphingosine, 1-sphingosine phosphate, phytosphingosine and phosphoethanolamine, which were belonged to the metabolism pathway of sphingolipid. Because of the function of OCT1 transporters was related with drug in the liver, the OCT1 1386C>A (rs 622342) was statistically significant (P<0.05) with IM plasma concentration. Thus, this study demonstrated that sphingolipid metabolism should be considered as the potential pathway of IM treated GISTs, which could bring us a clue to new mechanism for IM treatment of patients with GISTs.