Development and validation of an HPLC-UV method for routine trough plasma concentration monitoring of imatinib in Chinese patients with gastrointestinal stromal tumor

Imatinib is the first-line medication for the treatment of advanced gastrointestinal stromal tumor (GIST). Due to the large inter-individual variability, it is recommended to monitor the trough plasma concentration of imatinib to ensure the efficacy and safety of imatinib therapy. In the present study, an HPLC-UV method was developed and validated for quantitating imatinib in the plasma of Chinese GIST patients. The samples were processed by protein precipitation and then mixed with a neutralizing agent (1.4 g K₂CO₃ and 0.65 g KCl dissolved in 5 mL ultrapure water). The chromatographic separation was performed on an InertSustain C₁₈ column (250 mm×4.6 mm, 5 µM) maintained at 40 ºC utilizing the mobile phase consisted of 25 mM NH₄H₂PO₄ (pH 8.0)–acetonitrile (61:39, v/v) at a flow rate of 1 mL/min, with an ultraviolet detector set at 265 nm. The method was fully validated according to the published guidelines. The plotted calibration curves were all linear within the range of 50 to 10 000 ng/mL. The validation results of the intra-day and inter-day accuracies and precisions ranged from –5.81% to 6.33%. The extraction recoveries were within the range of 92.38% to 97.86%. All the results of stability studies were all consistent with the acceptance criteria of within ±15%. Finally, the method was successfully applied to trough plasma concentration monitoring of imatinib in 150 Chinese GIST patients orally administrated with imatinib. Incurred sample reanalysis was conducted, results of which were also in accordance with the acceptance criteria of within ±20%.     

Novel treatment of ovarian cancer cell lines with Imatinib mesylate combined with Paclitaxel and Carboplatin leads to receptor-mediated antiproliferative effects

Purpose  Imatinib is a small molecule inhibiting the tyrosine kinases bcr-abl, c-kit, PDGFR-α and PDGFR-β. Investigations were performed to screen ovarian cancer cell lines and tumor samples for target receptor expression. Effects of Imatinib on cell proliferation and apoptosis induction were measured with and without additional cytotoxic agents. Methods  Expression patterns of abl, c-kit, PDGFR-α and PDGFR-β (Imatinib targets) were studied in 5 cell lines and 111 tissue arrays by PCR and immunohistochemistry. Proliferation assays were performed with single agent Imatinib or combined with Paclitaxel and Carboplatin. Apoptosis was measured by DNA fragmentation. Results  All cell lines expressed abl and PDGFR-β. C-kit was only expressed in 2/5 cell lines and PDGFR-α in 4/5. Imatinib reduced cell growth and lead to pro-apoptotic changes. Combination of Carboplatin, Paclitaxel and Imatinib showed synergistic activity. Conclusions  Our results suggest that Imatinib may be useful for the specific treatment of ovarian cancer as an add-on to conventional chemotherapy. C. Mundhenke and M. T. Weigel contributed equally to this work.     

中高度复发风险胃肠间质瘤术后伊马替尼辅助治疗的疗效观察

目的 探讨伊马替尼（IM）对中高度复发风险胃肠道间质瘤（GIST）患者的术后辅助治疗疗效及其优化措施.方法 回顾性分析2004年1月至2012年9月间接受R0手术切除的连续225例中高危原发GIST患者（中危62例,高危163例）的临床及随访资料,比较接受IM辅助治疗及未接受IM辅助治疗两组患者的术后复发情况.结果 在中危GIST患者中,服药组与未服药组相比,5年无复发生存率（RFS）分别为83.3%和88.6%,两组生存曲线差异无统计学意义（P=0.647）;高危GIST患者中,服药组与未服药组术后1年的RFS分别为93.5%和81.2%,差异有统计学意义（P=0.037）,而术后5年RFS分别为56.1%和50.2%,两组生存曲线比较差异无统计学意义（P=0.112）;此外,在高危GIST患者中,核分裂象＞10/HPF或有局部浸润的服药组和未服药组患者比较,服药组术后1年的复发率均显著低于未服药组,P值分别为0.022和0.036,而核分裂相≤10/HPF且无局部浸润的服药和未服药组患者术后1年的复发率差异无统计学意义（P=0.789）.结论 GIST术后IM辅助治疗可有效延缓肿瘤复发,但不能预防IM停药后的肿瘤复发,对于核分裂象＞10/HPF或伴有局部浸润的高危GIST患者,应尽量延长术后IM的辅助治疗时间.     

舒尼替尼治疗伊马替尼耐药胃肠间质瘤的疗效及安全性分析

目的探讨舒尼替尼治疗伊马替尼耐药胃肠间质瘤（GIST）的疗效及安全性。方法回顾性分析2008年5月至2012年4月间在福建医科大学附属协和医院接受舒尼替尼治疗的48例伊马替尼耐药GIST患者的临床资料。舒尼替尼用药方案：18例患者采用50mg／d服药4周,停药2周（50mg／d4／2组）;30例患者采用37．5mg／d连续口服（37．5mg／dCDD组）。结果48例患者舒尼替尼中位治疗时间为56周．按Choi标准于治疗后24周进行近期疗效评估．获完全缓解1例,部分缓解12例,疾病稳定21例,疾病进展14例,客观有效率为27．1％（13／48）,疾病控制率为70．8％（34／48）。48例患者中位随访时间为89周,中位无进展生存期（PLUS）为48周,中位总体生存期（OS）为92周。分组分析显示：既往伊马替尼剂量为400mg／d者,其PFS和Os均优于既往伊马替尼剂量大于400mg／d者（中位PFS：53比35周,P=0．018;中位OS：157比71周,P=0．003）;外显子11突变者0s劣于外显子9突变者（中位0s：71比157周,P=O．008）。治疗期间的主要不良反应有手足综合征（25例,52．1％）、恶心（24例,50．0％）、疲乏（23例,47．9％）和中性粒细胞减少（21例,43．7％）。按舒尼替尼给药方案分组分析,50mg／d4／2组腹泻及手足综合征的发生情况较37．5mg／dCDD组更为严重（P=0．027,P=0．048）。结论舒尼替尼治疗伊马替尼耐药的GIST疗效较好。在伊马替尼400mg／d耐药后应直接换用舒尼替尼而不要加大伊马替尼用药剂量。外显子9突变者舒尼替尼的治疗效果优于外显子11突变者。舒尼替尼37．5mg／d连续口服的用药方案安全性较好。     

Antagonist activity of the antipsychotic drug lithium chloride and the antileukemic drug imatinib mesylate during glioblastoma treatment in vitro

Objectives: Glioblastoma (GBM), the most common primary tumour of the central nervous system, is characterised by a high malignancy and poor prognosis. The aims of this study were to investigate whether the combination of imatinib mesylate (IM) and lithium chloride (LiCl) exhibited a synergistic effect in treatment and to determine whether midkine (MK) affected the fate of this treatment in vitro.

Methods: Monolayer and spheroid cultures of the T98G human GBM cell line were treated with an IM and LiCl combination for 72 h. The cell proliferation index, apoptotic index, cell cycle distribution, apoptotic and anti-apoptotic protein levels, and cAMP level as well as the cellular morphology and ultrastructure were evaluated.

Results: All applications inhibited cell proliferation and induced apoptosis. The most substantial decreases in cell proliferation and the caspase-3, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor-alpha (PDGFR-α), multidrug resistance protein-1 (MRP-1), aquaporin-4 (AQP-4) and cAMP levels were induced by the LiCl treatment, which exhibited more pronounced effects compared with the combination treatment. LiCl was less effective in decreasing the MK and B cell lymphoma-2 (Bcl-2) levels compared with the combination treatment. The most substantial decrease in the p170 levels was identified following the combination treatment, whereas IM induced the second greatest decrease. LiCl alone had no effect on the p170 levels. IM induced the most substantial decrease in the phospho-glycogen synthase kinase 3-beta (p-GSK-3β)/glycogen synthase kinase 3-beta (GSK-3β) ratio, and LiCl induced the second most substantial decrease. Both LiCl and the combination treatment induced G2 + M arrest, whereas IM induced G0 + G1 arrest after 72 h of exposure. An apoptotic appearance and autophagic vacuoles were commonly identified in the LiCl, combination and IM groups, respectively.

Conclusions: The combination of IM and LiCl exhibited an antagonist effect, and MK had a role at this antagonism.     

胃间质瘤的诊断及治疗进展

近年来胃肠道肿瘤的检出率的提高,胃间质瘤受到广泛关注。目前胃间质瘤的诊断仍然依赖内镜及医学影像学检查,治疗上除了强调手术的重要性,同时也突出了分子靶向药物的疗效。胃间质瘤的诊断技术在传统检查基础上有所更新,分子靶向药物的临床实践初见成效,但其耐药情况及二、三线靶向药物治疗仍缺乏大量的循证医学证据。本文将就目前胃间质瘤的诊疗及治疗进行综述。     

细胞内伊马替尼浓度在胃肠道间质瘤耐药过程中的作用

目的探讨细胞内伊马替尼浓度与胃肠道间质瘤（GIST）耐药性的关系。 方法随机选择南京医科大学第一附属医院2014年12月至2016年4月伊马替尼耐药和敏感的进展期GIST患者各4例,采用液相色谱-串联质谱法（LC-MS/MS）检测细胞内外、组织内与血浆伊马替尼浓度。苏木精-伊红染色和免疫组织化学法观察细胞的形态特征。 结果伊马替尼耐药患者组织内药物浓度比敏感患者的组织内药物浓度低（P<0.05）。与亲代敏感细胞株相比,伊马替尼耐药GIST细胞株中细胞内伊马替尼浓度显著降低,同时细胞形态也发生了变化。 结论低细胞内药物浓度可能是伊马替尼耐药的重要原因,细胞内伊马替尼浓度可能是治疗GIST过程中的关键要素。     

Successful Treatment of Idiopathic Hypereosinophilic Syndrome with Imatinib Mesylate: A Case Report

Patients with idiopathic hypereosinophilic syndrome (HES) show persistent hypereosinophilia of unknown etiology that is associated with end-organ damage. Different treatments, including the use of corticosteroids and cytotoxics, have been investigated for HES with modest success. We describe a patient with HES who had significant end-organ damage from hypereosinophilia and remained refractory to conventional therapy. Therapy with imatinib mesylate, a selective tyrosine kinase inhibitor that is highly effective in treating patients with BCR-ABL-positive chronic myeloid leukemia, was tried with the patient. The result was impressive, with hematologic remission achieved after 12 days of administration. Our finding concurs with recent reports that imatinib mesylate may be a promising agent in the treatment of some cases of HES.     

Severe Hepatic Injury Caused by Imatinib Mesylate Administered for the Treatment of Chronic Myeloid Leukemia and the Efficacy of Prednisolone for its Management

Imatinib mesylate is a specific inhibitor of BCR-ABL tyrosine kinase, which is now widely used for the treatment of chronic myeloid leukemia (CML) with a high efficacy. Although severe hepatic injury caused by imatinib mesylate is rare, such a side effect may force patients to discontinue taking imatinib mesylate. In the present paper, we report on the case of a 51-year-old woman with CML who experienced hepatic injury with severe hyperbilirubinemia caused by imatinib mesylate. The findings from a liver biopsy specimen and her clinical course suggested the hepatic injury to presumably have been caused by an allergic mechanism. The co-administration of prednisolone was thus tried, and she has been able to continue imatinib mesylate administration without any liver dysfunction and finally was able to obtain a complete cytogenetic response.We therefore recommend that prednisolone should be tried when severe hepatic injury caused by imatinib mesylate is observed, since it might enable such patients to continue imatinib mesylate treatment and thereby improve the prognosis in such cases.     

胃肠道间质瘤伊马替尼术前治疗进展

目的 探讨伊马替尼术前治疗胃肠道间质瘤（gastrointestinal stromal tumor,GIST）的作用。 方法 采用文献复习的方法,对研究伊马替尼术前治疗GIST的文献加以综述。 结果 伊马替尼术前治疗是进展期GIST的有效治疗手段,能显著提高患者的手术切除率,延长总体生存时间。 结论 术前伊马替尼治疗转移性或局部进展期GIST疗效较好,应参考GIST基因分型结果个体化术前给药,值得进一步深入临床研究。