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Combination of ionizing radiation and 2-thio-6-azauridine induces cell death in radioresistant triple negative breast cancer cells by downregulating CD151 expression. 电离辐射和 2-硫代-6-氮尿嘧啶联合使用可通过下调 CD151 的表达诱导耐放射性三阴性乳腺癌细胞死亡。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-21 DOI: 10.1007/s00280-024-04709-w
Rakshmitha Marni, Manas Malla, Anindita Chakraborty, Murali Krishna Voonna, Partha Sarathi Bhattacharyya, Deepak Kgk, Rama Rao Malla

Background: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer and is frequently resistant to therapy, ultimately resulting in treatment failure. Clinical trials have demonstrated the potential of sensitizing radiation therapy (RT)-resistant TNBC through the combination of chemotherapy and RT. This study sought to explore the potential of CD151 as a therapy response marker in the co-treatment strategy involving ionizing radiation (IR) and the repurposed antiviral drug 2-Thio-6-azauridine (TAU) for sensitizing RT-resistant TNBC (TNBC/RR).

Methods: The investigation encompassed a variety of assessments, including viability using MTT and LDH assays, cell proliferation through BrdU incorporation and clonogenic assays, cell cycle analysis via flow cytometry, cell migration using wound scratch and Boyden chamber invasion assays, DNA damage assessment through γH2AX analysis, apoptosis evaluation through acridine-orange and ethidium bromide double staining assays, as well as caspase 3 activity measurement using a colorimetric assay. CD151 expression was examined through ELISA, flow cytometry and RT-qPCR.

Results: The results showed a significant reduction in TNBC/RR cell viability following co-treatment. Moreover, the co-treatment reduced cell migration, induced apoptosis, downregulated CD151 expression, and increased caspase 3 activity in TNBC/RR cells. Additionally, CD151 was predicted to serve as a therapy response marker for co-treatment with TAU and IR.

Conclusion: These findings suggest the potential of combination treatment with IR and TAU as a promising strategy to overcome RT resistance in TNBC. Furthermore, CD151 emerges as a valuable therapy response marker for chemoradiotherapy.

背景三阴性乳腺癌(TNBC)是乳腺癌中最具侵袭性的亚型,经常对治疗产生耐药性,最终导致治疗失败。临床试验表明,通过化疗和 RT 的联合治疗,有可能使放射治疗(RT)耐药的 TNBC 增敏。本研究试图探索CD151在电离辐射(IR)和再利用抗病毒药物2-硫代-6-氮尿嘧啶(TAU)联合治疗策略中作为治疗反应标志物的潜力,以增敏RT耐药的TNBC(TNBC/RR):调查包括多种评估,其中包括使用 MTT 和 LDH 检测法评估细胞存活率;使用 BrdU 结合和克隆生成检测法评估细胞增殖;使用流式细胞仪分析细胞周期;使用伤口划痕和 Boyden 室侵袭检测法评估细胞迁移;使用 γH2AX 分析法评估 DNA 损伤;使用吖啶橙和溴化乙锭双重染色检测法评估细胞凋亡;以及使用比色法测量 Caspase 3 活性。通过酶联免疫吸附、流式细胞术和 RT-qPCR 检测 CD151 的表达:结果表明,联合治疗后 TNBC/RR 细胞活力明显降低。此外,联合处理还能减少 TNBC/RR 细胞的迁移、诱导细胞凋亡、下调 CD151 的表达和增加 caspase 3 的活性。此外,CD151被预测为TAU和IR联合治疗的治疗反应标志物:这些研究结果表明,IR和TAU联合治疗有望成为克服TNBC RT耐药的一种策略。此外,CD151还是化放疗的一个有价值的治疗反应标志物。
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引用次数: 0
Relative bioavailability and food effect of the galectin-3 inhibitor selvigaltin (GB1211) administered as a tablet in healthy participants (GALBA-1). 以片剂形式给健康参与者服用的galectin-3抑制剂selvigaltin(GB1211)的相对生物利用度和食物效应(GALBA-1)。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-21 DOI: 10.1007/s00280-024-04710-3
Vassilios Aslanis, Khalid Abd-Elaziz, Robert J Slack, Anne Brinch, Lise Gravelle, Wayne Morley, De Phung, Kimberly Herman, Ian Holyer, Karen Killerup Poulsen, Peter Dogterom, Susan Tantawi, Fredrik R Zetterberg, Brian Jacoby, Hans Schambye, Bertil Lindmark

Purpose: Overexpression of galectin-3, a β-galactoside-binding lectin, is associated with fibrotic diseases and cancer. Selvigaltin is an oral galectin-3 inhibitor, previously administered as a 50 mg capsule. This study aimed to evaluate the relative bioavailability and food effect of selvigaltin as a 100 mg tablet in healthy volunteers.

Methods: In this single-dose, randomized, three-period, crossover study (GALBA-1; NCT05747573), participants received selvigaltin as a 100 mg tablet (under fasted and fed conditions) or as two 50 mg capsules (under fasted conditions). Primary endpoints included plasma and urine pharmacokinetic (PK) parameters. Secondary endpoints were safety and tolerability.

Results: Of the 13 enrolled participants, 12 completed the study. Under fasted conditions, geometric mean maximum observed plasma concentration (Cmax) and systemic exposure (AUC0─inf) of selvigaltin were 161.0% and 84.0% higher, respectively, after administration of a tablet vs. capsules. Under fed vs. fasted conditions, geometric mean Cmax of the selvigaltin tablet was 20.0% lower, whereas AUC0─inf was unaffected. Geometric mean percentage of total dose of selvigaltin excreted in urine over 0─96 h was 30.3% and 35.9% for the tablet under fasted and fed conditions, respectively, and 14.5% for the capsules. No treatment-emergent severe or serious adverse events or study discontinuations due to a treatment-emergent adverse event were reported.

Conclusion: The tablet formulation of selvigaltin displayed higher bioavailability vs. the capsule formulation, with minimal effect of food on PK. Selvigaltin was well-tolerated during all treatments. These findings warrant further clinical development of the tablet formulation of selvigaltin without specific food restrictions.

Clinical trial registration: NCT05747573; February 28, 2023.

目的:galectin-3 是一种 β-半乳糖苷结合凝集素,它的过度表达与纤维化疾病和癌症有关。Selvigaltin是一种口服galectin-3抑制剂,以前以50毫克胶囊的形式给药。本研究旨在评估健康志愿者服用 100 毫克片剂塞尔维加尔汀的相对生物利用度和食物效应:在这项单剂量、随机、三期交叉研究(GALBA-1;NCT05747573)中,参与者服用的是 100 毫克片剂(空腹和进食条件下)或两粒 50 毫克胶囊(空腹条件下)。主要终点包括血浆和尿液药代动力学(PK)参数。次要终点为安全性和耐受性:结果:13 名参加者中,12 人完成了研究。在空腹条件下,服用片剂与胶囊相比,舍维加尔汀的几何平均最大观察血浆浓度(Cmax)和全身暴露量(AUC0─inf)分别高出161.0%和84.0%。在进食与禁食条件下,舍维加尔汀片剂的几何平均Cmax降低了20.0%,而AUC0─inf则不受影响。在空腹和进食条件下,片剂在0-96小时内从尿液中排出的舍维加尔汀占总剂量的几何平均百分比分别为30.3%和35.9%,胶囊则为14.5%。未报告因治疗引起的严重不良事件或研究中止:结论:与胶囊剂相比,片剂的生物利用度更高,食物对PK的影响最小。在所有治疗过程中,塞尔维加尔汀的耐受性都很好。这些研究结果证明,在没有特定食物限制的情况下,可以进一步临床开发舍维加尔汀片剂:临床试验注册:NCT05747573;2023年2月28日。
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引用次数: 0
Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects. 新型ALK酪氨酸激酶抑制剂[14C]envonalkib(TQ-B3139)在中国健康受试者中的药代动力学、质量平衡和代谢。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-03-20 DOI: 10.1007/s00280-024-04647-7
Sheng Ma, Xin Wang, Shu Yan, Liyan Miao, Xiaojing Wan, Dawei Ding, Ding Yu, Xingxing Diao, Xunqiang Wang, Hua Zhang

Purpose: Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects.

Methods: A single oral dose of 600 mg (150 µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification.

Results: After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study.

Conclusion: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.

目的:Envonalkib(TQ-B3139)是一种新型、强效的无性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂,用于治疗ALK阳性的非小细胞肺癌。这项 I 期质量平衡研究调查了中国健康男性受试者体内 14C 放射性标记的恩沃纳克的药代动力学、代谢和排泄情况:方法:健康男性受试者在空腹状态下单次口服 600 毫克(150 µCi)[14C]envonalkib。收集血液、尿液和粪便样本,定量测定总放射性和未改变的烯沃纳基布,并对代谢物进行鉴定:结果:用药后,血浆中放射性的中位Tmax为4小时,平均t1/2为65.2小时。血浆中总放射性的暴露量远高于未改变的恩沃那昔。在给药后的504小时内,放射性标记剂量的平均总回收率为93.93%,其中尿液中的回收率为15.23%,粪便中的回收率为78.71%。恩沃那昔经过大量代谢,在血浆、尿液和粪便中总共发现了15种代谢物。未发生变化的恩沃那昔及其主要代谢物M315是血浆中的主要成分,分别占血浆总放射性的20.37%和33.33%。在尿液中,O-脱烷基代谢物 M315 是主要成分,占剂量的 7.98%。在粪便中,16.01%的剂量以半胱氨酸共轭物M434-1的形式排出。恩沃那麒耐受性良好,研究中未发现严重不良反应:结论:恩沃那珂布在排泄前被广泛代谢,主要以代谢物的形式经粪便排出体外。
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引用次数: 0
Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer. 晚期癌症患者使用低剂量 nivolumab(相对于常规剂量)的药代动力学和临床疗效。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-26 DOI: 10.1007/s00280-024-04697-x
Khushboo A Gandhi, Aditi Shirsat, Sharat Kumar Hj, Ashish Chavan, Parnika Dicholkar, Saniya Shah, Nandini Menon, Vanita Noronha, Amit Joshi, Kumar Prabhash, Vijay Patil, Vikram Gota

Purpose: Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses.

Methods: Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity.

Results: Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized Cmax and AUC0-t were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group.

Conclusion: Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.

目的:Nivolumab获批的剂量多种多样,包括3毫克/千克、240毫克和480毫克的平剂量以及不同的给药间隔。近年来,低剂量免疫疗法的概念正日益受到重视。然而,我们需要更好地了解低剂量时的药代动力学和临床效果:方法:根据医院的现行做法,根据患者的经济承受能力,为患者注射 40 毫克的固定剂量或 3 毫克/千克的 Q2W/Q3W 剂量。所有患者均在第 1 天住院,并在服用首剂尼夫单抗后的 0、0.5、1.0、6.0、24.0、72.0 h 和第 14 天采集药代动力学样本。通过酶联免疫吸附法测定血浆中的尼夫单抗水平。对患者的反应和毒性进行随访:研究共纳入了 25 名患者。14名患者接受了常规剂量(3毫克/千克)的尼伏单抗治疗,11名患者接受了低剂量(40毫克平片)的尼伏单抗治疗。接受常规剂量和低剂量nivolumab的患者的剂量归一化Cmax和AUC0-t的几何平均数相当(分别为0.28对0.23 µg/mL/mg和0.0014对0.0011 d/mL)。19名患者的反应可进行评估。接受常规剂量治疗的患者的ORR为5/11(45.5%),而低剂量队列中的ORR为4/9(44.4%)。常规剂量组的所有 14 名患者(100%)和低剂量组的 7/11 名患者(63.64%)都出现了治疗突发不良事件。常规剂量组有4/14例患者出现≥3级毒性反应,低剂量组无:结论:与常规剂量相比,低剂量nivolumab导致患者的暴露量更低,但低剂量的耐受性更好,而反应率与常规剂量相当。
{"title":"Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer.","authors":"Khushboo A Gandhi, Aditi Shirsat, Sharat Kumar Hj, Ashish Chavan, Parnika Dicholkar, Saniya Shah, Nandini Menon, Vanita Noronha, Amit Joshi, Kumar Prabhash, Vijay Patil, Vikram Gota","doi":"10.1007/s00280-024-04697-x","DOIUrl":"10.1007/s00280-024-04697-x","url":null,"abstract":"<p><strong>Purpose: </strong>Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses.</p><p><strong>Methods: </strong>Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity.</p><p><strong>Results: </strong>Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized C<sub>max</sub> and AUC<sub>0-t</sub> were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group.</p><p><strong>Conclusion: </strong>Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Selinexor targeting XPO1 promotes PEG3 nuclear accumulation and suppresses cholangiocarcinoma progression. 以 XPO1 为靶点的 Selinexor 可促进 PEG3 的核积累并抑制胆管癌的进展。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-05 DOI: 10.1007/s00280-024-04704-1
Deng Xiang, Min Wang, Huajun Wu, Xi Chen, Tianxiang Chen, Dongshan Yu, Lei Xiong, Han Xu, Ming Luo, Shouhua Zhang, Linquan Wu, Jinlong Yan

Background: The role of selinexor, a targeted inhibitor of exportin 1 (XPO1), in the treatment of cholangiocarcinoma is not yet fully understood. This study conducted comprehensive in vitro and in vivo investigations to elucidate the effects of selinexor on cholangiocarcinoma, with a focus on its mechanistic relationship with the cellular localization of Paternally Expressed Gene 3 (PEG3).

Methods: A patient-derived xenograft (PDX) model was established using samples from a cholangiocarcinoma patient in immunodeficient mice to assess the in vivo effects of selinexor. Additionally, cholangiocarcinoma cell lines HuCC-T1 and BRE were cultured to evaluate selinexor's impact on cell proliferation, invasion, migration, cell cycle, and apoptosis. HuCC-T1 cells were also implanted in immunodeficient mice for further investigation. Immunofluorescence and Western blotting were employed to observe the expression and localization of the PEG3 protein.

Results: The results demonstrated that selinexor significantly inhibited tumor growth in the cholangiocarcinoma PDX model and promoted the accumulation of PEG3 protein within the nuclei of tumor cells. In vitro experiments showed that selinexor effectively suppressed cholangiocarcinoma cell proliferation, invasion, and migration, while also impeding the cell cycle and inducing apoptosis. Notably, selinexor markedly facilitated the nuclear accumulation of PEG3 protein in cholangiocarcinoma cells. However, when PEG3 expression was knocked down, the effects of selinexor on cholangiocarcinoma were significantly reversed.

Conclusion: These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.

背景:selinexor是一种输出蛋白1(XPO1)靶向抑制剂,它在治疗胆管癌中的作用尚未完全明了。本研究进行了全面的体外和体内研究,以阐明 selinexor 对胆管癌的影响,重点研究其与父系表达基因 3 (PEG3) 细胞定位的机理关系:方法:利用免疫缺陷小鼠中的胆管癌患者样本建立了患者衍生异种移植(PDX)模型,以评估selinexor的体内效应。此外,还培养了胆管癌细胞系 HuCC-T1 和 BRE,以评估 selinexor 对细胞增殖、侵袭、迁移、细胞周期和凋亡的影响。还将 HuCC-T1 细胞植入免疫缺陷小鼠体内进行进一步研究。采用免疫荧光和 Western 印迹技术观察 PEG3 蛋白的表达和定位:结果表明,selinexor能显著抑制胆管癌PDX模型的肿瘤生长,并促进PEG3蛋白在肿瘤细胞核内的积累。体外实验表明,selinexor能有效抑制胆管癌细胞的增殖、侵袭和迁移,同时还能阻碍细胞周期并诱导细胞凋亡。值得注意的是,selinexor 能明显促进 PEG3 蛋白在胆管癌细胞核内的积累。然而,当 PEG3 的表达被敲除时,selinexor 对胆管癌的影响就会明显逆转:这些研究结果表明,selinexor 通过靶向 XPO1 和促进 PEG3 蛋白的核积累,从而阻碍细胞周期并诱导细胞凋亡,从而抑制胆管癌的进展。
{"title":"Selinexor targeting XPO1 promotes PEG3 nuclear accumulation and suppresses cholangiocarcinoma progression.","authors":"Deng Xiang, Min Wang, Huajun Wu, Xi Chen, Tianxiang Chen, Dongshan Yu, Lei Xiong, Han Xu, Ming Luo, Shouhua Zhang, Linquan Wu, Jinlong Yan","doi":"10.1007/s00280-024-04704-1","DOIUrl":"10.1007/s00280-024-04704-1","url":null,"abstract":"<p><strong>Background: </strong>The role of selinexor, a targeted inhibitor of exportin 1 (XPO1), in the treatment of cholangiocarcinoma is not yet fully understood. This study conducted comprehensive in vitro and in vivo investigations to elucidate the effects of selinexor on cholangiocarcinoma, with a focus on its mechanistic relationship with the cellular localization of Paternally Expressed Gene 3 (PEG3).</p><p><strong>Methods: </strong>A patient-derived xenograft (PDX) model was established using samples from a cholangiocarcinoma patient in immunodeficient mice to assess the in vivo effects of selinexor. Additionally, cholangiocarcinoma cell lines HuCC-T1 and BRE were cultured to evaluate selinexor's impact on cell proliferation, invasion, migration, cell cycle, and apoptosis. HuCC-T1 cells were also implanted in immunodeficient mice for further investigation. Immunofluorescence and Western blotting were employed to observe the expression and localization of the PEG3 protein.</p><p><strong>Results: </strong>The results demonstrated that selinexor significantly inhibited tumor growth in the cholangiocarcinoma PDX model and promoted the accumulation of PEG3 protein within the nuclei of tumor cells. In vitro experiments showed that selinexor effectively suppressed cholangiocarcinoma cell proliferation, invasion, and migration, while also impeding the cell cycle and inducing apoptosis. Notably, selinexor markedly facilitated the nuclear accumulation of PEG3 protein in cholangiocarcinoma cells. However, when PEG3 expression was knocked down, the effects of selinexor on cholangiocarcinoma were significantly reversed.</p><p><strong>Conclusion: </strong>These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacokinetics of trastuzumab and its efficacy and safety in HER2-positive cancer patients. 曲妥珠单抗的药代动力学及其对 HER2 阳性癌症患者的疗效和安全性。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-23 DOI: 10.1007/s00280-024-04707-y
Xinyu Luo, Nan Wang, Yue Xing, Xinyue Gao, Yang Yu, Tong Liu, Shuai Jiang, Mei Dong

Trastuzumab is a potent targeted therapy drug for HER2-positive cancer patients. A comprehensive understanding of trastuzumab's mechanism of action, pharmacokinetic (PK) parameters, and steady-state exposure in different treatment regimens and administration routes is essential for a thorough evaluation of the drug's safety and effectiveness. Due to the distinctive pharmacokinetics, indications, and administration methods of trastuzumab, this understanding becomes crucial. Drug exposure can be assessed by measuring trastuzumab's peak concentration, trough concentration, or area under the curve through assays like enzyme-linked immunosorbent assay (ELISA) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). The dose-response (D-R) and exposure-response (E-R) relationships establish the correlation between drug dosage/exposure and the therapeutic effect and safety. Additionally, various covariates such as body weight, aspartate transaminase, and albumin levels can influence drug exposure. This review provides a comprehensive overview of trastuzumab's mechanism of action, data on steady-state concentration and PK parameters under multiple administration routes and indications, discussions on factors influencing PK parameters, and evaluations of the effectiveness and safety of E-R and D-R in diverse HER2-positive cancer patients.

曲妥珠单抗是一种针对 HER2 阳性癌症患者的强效靶向治疗药物。全面了解曲妥珠单抗的作用机制、药动学(PK)参数以及不同治疗方案和给药途径下的稳态暴露量,对于彻底评估该药物的安全性和有效性至关重要。由于曲妥珠单抗的药代动力学、适应症和给药方法各不相同,因此了解其药代动力学至关重要。药物暴露可通过酶联免疫吸附试验(ELISA)或液相色谱-串联质谱法(LC-MS/MS)等检测方法测量曲妥珠单抗的峰浓度、谷浓度或曲线下面积来评估。剂量-反应(D-R)和暴露-反应(E-R)关系确定了药物剂量/暴露与治疗效果和安全性之间的相关性。此外,体重、天冬氨酸转氨酶和白蛋白水平等各种协变量也会影响药物暴露。本综述全面概述了曲妥珠单抗的作用机制、多种给药途径和适应症下的稳态浓度和 PK 参数数据、PK 参数影响因素讨论,以及 E-R 和 D-R 在不同 HER2 阳性癌症患者中的有效性和安全性评估。
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引用次数: 0
An interactive dose optimizer based on population pharmacokinetic study to guide dosing of methotrexate in Chinese patients with osteosarcoma. 基于群体药代动力学研究的交互式剂量优化器,用于指导中国骨肉瘤患者的甲氨蝶呤用药。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-24 DOI: 10.1007/s00280-024-04708-x
Yanjie Zhang, Xiemin Qi, Xiaohui Huang, Xiaozhou Liu, Yanyu Liu, Jianzhong Rui, Qiong Yin, Sujia Wu, Guohua Zhou

Purpose: Osteosarcoma is a rare tumor with an incidence of 4.4 cases per million per year in adolescent. High-dose methotrexate (HD-MTX) is the standard first-line chemotherapeutic agent for osteosarcoma. However, its efficacy can vary significantly among individuals due to wide pharmacokinetic variability. Despite this, only a few population pharmacokinetics (popPK) models based on Chinese patients with osteosarcoma have been reported. Thus, this study aimed to develop a HD-MTX popPK model and an individual model-based dose optimizer for osteosarcoma therapy.

Method: A total of 680 MTX serum concentrations from 57 patients with osteosarcoma were measured at the end of MTX infusion and 10 h, 24 h, 48 h, and 72 h after the start of infusion. Using the first-order conditional estimation method with NONMEM, a popPK model was estimated. Goodness-of-fit plots, visual predictive checks, and bootstrap analysis were generated to evaluate the final model. A dose optimizer tool was developed based on the validated models using R Shiny. Additionally, clinical data from 12 patients with newly diagnosed osteosarcoma were collected and used as the validation set to preliminarily verify the predictive ability of the popPK model and the dose optimizer tool.

Results: Body surface area (BSA) was the most significant covariate for compartment distribution. Creatinine clearance (CrCL) and co-administration of NSAIDs were introduced as predictors for central compartmental and peripheral compartmental clearance, respectively. Co-administration of NSAIDs was associated with significantly higher MTX concentrations at 72 h (p = 0.019). The dose optimizer tool exhibited a high consistency in predicting MTX AUC compared to the actual AUC (r = 0.821, p < 0.001) in the validation set.

Conclusion: The dose optimizer tool could be used to estimate individual PK parameters, and optimize personalized MTX therapy in particular patients.

目的:骨肉瘤是一种罕见肿瘤,在青少年中的发病率为每年每百万人中4.4例。大剂量甲氨蝶呤(HD-MTX)是治疗骨肉瘤的标准一线化疗药物。然而,由于药代动力学的广泛变异性,其疗效在个体之间会有很大差异。尽管如此,基于中国骨肉瘤患者的群体药代动力学(popPK)模型却鲜有报道。因此,本研究旨在建立 HD-MTX popPK 模型和基于个体模型的骨肉瘤治疗剂量优化器:方法:在MTX输注结束时、输注开始后10小时、24小时、48小时和72小时测量了57名骨肉瘤患者的680个MTX血清浓度。利用 NONMEM 的一阶条件估计法,对 popPK 模型进行了估计。生成拟合优度图、视觉预测检查和引导分析来评估最终模型。根据验证过的模型,使用 R Shiny 开发了一个剂量优化工具。此外,还收集了 12 名新确诊骨肉瘤患者的临床数据作为验证集,以初步验证 popPK 模型和剂量优化工具的预测能力:体表面积(BSA)是影响分区分布的最重要的协变量。肌酐清除率(CrCL)和同时服用非甾体抗炎药分别是中心区室和外周区室清除率的预测因子。联合使用非甾体抗炎药与 72 小时内 MTX 浓度显著升高有关(p = 0.019)。与实际AUC相比,剂量优化工具在预测MTX AUC方面表现出较高的一致性(r = 0.821,p 结论):剂量优化工具可用于估计个体 PK 参数,并优化特定患者的个性化 MTX 治疗。
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引用次数: 0
Successful desensitization in a patient with metastatic colorectal cancer presenting with regorafenib-mediated fix drug eruption. 成功对一名出现瑞戈非尼介导的固定药物爆发的转移性结直肠癌患者进行脱敏治疗。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-19 DOI: 10.1007/s00280-024-04719-8
Hazal Kayikci, C Tuccar, E Damadoglu, G Karakaya, A F Kalyoncu

Introduction: Regorafenib is an oral protein kinase inhinitor approved fot the treatment of metastatic colorecral cancer. We present a first successful case of desensitization in regorafenib-related fix-drug eruption in the literature.

Case report: A 44-year-old female patient was diagnosed with metastatic colorectal adenocarcinoma. The patient received regorafenib treatment for malignancy recurrence. The patient was admitted to adult allergy clinic with developing recurrent fix drug eruption in the second cycle, on the 10th day of regorafenib treatment. The patient was given the third cycle of regorafenib treatment with a 6-day desensitization protocol, the first day of which consisted of 6 steps and and the third cycle was successfully completed.

Management and outcome: Regorafenib-mediated delayed hypersensitivity reactions occur less frequently and and regorafenib hypersensitivity reactions are difficult to manage and experience is limited. This is the first successful desensitization protocol developed by us for regorafenib-related fix drug eruption and more cases are needed to be reported to confirm the desensitization protocol.

Discussion: There is only one successful regorafenib desensitization protocol for severe delayed hypersensivity reaction in the literature, but there is no protocol developed for mild type delayed hypersensivity reaction. The management of fix-drug eruption primarily involves discontinuation and avoidance of the offending drug but our patient had a mild delayed-type reaction and there was no alternative to regarofenib treatment. We developed the rapid 6-step desensitization protocol (Day 1). According to this protocol, the patient was able to continue regorafenib treatment successfully.

简介瑞戈非尼是一种口服蛋白激酶抑制剂,被批准用于治疗转移性结肠癌。我们在文献中首次成功报道了一例瑞戈非尼相关固定药疹的脱敏治疗:病例报告:一名 44 岁的女性患者被诊断为转移性结直肠腺癌。患者因恶性肿瘤复发接受了瑞戈非尼治疗。在瑞戈非尼治疗的第 10 天,患者因在第二周期出现复发性固定药物疹而入住成人过敏门诊。患者在接受瑞戈非尼治疗的第三个周期时,接受了为期6天的脱敏方案,其中第一天包括6个步骤,并顺利完成了第三个周期的治疗:瑞戈非尼介导的迟发性超敏反应发生率较低,瑞戈非尼超敏反应难以处理,经验有限。这是我们针对瑞戈非尼相关固定药物爆发制定的首个成功脱敏方案,还需要更多病例的报道来证实该脱敏方案:讨论:文献中只有一个成功的瑞戈非尼脱敏方案用于重度迟发性过敏反应,但还没有针对轻度迟发性过敏反应的脱敏方案。固定药物疹的治疗方法主要是停用和避免使用违规药物,但我们的患者属于轻度延迟型反应,除了瑞戈非尼治疗外别无选择。我们制定了快速 6 步脱敏方案(第 1 天)。根据该方案,患者成功地继续接受了瑞戈非尼治疗。
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引用次数: 0
An intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in patients with metastatic or primary brain tumors. 一项脑内微透析研究,旨在确定艾瑞布林在转移性或原发性脑肿瘤患者中的神经药代动力学。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-18 DOI: 10.1007/s00280-024-04711-2
Zeynep Eroglu, Timothy Synold, Behnam Badie, An Liu, Arnab Chowdhury, Julie Kilpatrick, Suzette Blanchard, Jana Portnow

Purpose: Eribulin is an inhibitor of microtubule dynamics. It is not as highly protein bound as the taxanes and is less vulnerable to extrusion by P-glycoprotein in the blood-brain barrier (BBB). These features predict that eribulin could play an active role in managing brain tumors. Indeed, the small amount of published clinical data indicates eribulin may have some efficacy against breast cancer brain metastases. To better understand the potential of eribulin for treating brain tumors, we performed an intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in cancer patients undergoing tumor resection.

Methods: After tumor removal, two microdialysis catheters were inserted into peritumoral brain tissue. Approximately 24 h after surgery, a single dose of eribulin 1.4 mg/m2 was administered intravenously. Dialysate samples were collected continuously for 72 h, with plasma samples collected in parallel. Eribulin concentrations were analyzed by tandem mass spectrometry.

Results: Dialysate samples from 12 intracerebral microdialysis catheters placed in 7 study participants were included in the analysis. A statistically significant difference was observed between eribulin concentrations in brain tissue where BBB was disrupted versus intact, with a difference in mean maximum concentrations on log2 scale of 3.37 (std err = 0.59, p-value = 0.005). Nonetheless, overall brain to plasma ratios of eribulin only ranged from 0.13 to 1.99%.

Conclusion: Although we could detect higher concentrations of eribulin in brain tissue where BBB was disrupted, intracerebral eribulin levels were not sufficient to predict eribulin would have consistent clinically meaningful activity against tumors in the brain.

Clinicaltrials:

Gov identifier: NCT02338037 (January 9, 2015).

目的:Eribulin 是一种微管动力学抑制剂。它不像紫杉类药物那样与蛋白质高度结合,在血脑屏障(BBB)中不易被P-糖蛋白挤出。这些特点预示着艾瑞布林可在治疗脑肿瘤方面发挥积极作用。事实上,已发表的少量临床数据表明,艾瑞布林对乳腺癌脑转移可能有一定疗效。为了更好地了解艾瑞布林治疗脑肿瘤的潜力,我们进行了一项脑内微透析研究,以确定艾瑞布林在接受肿瘤切除术的癌症患者中的神经药代动力学:肿瘤切除后,将两根微透析导管插入瘤周脑组织。手术后约 24 小时,静脉注射单剂量艾瑞布林 1.4 mg/m2。连续收集透析液样本72小时,同时收集血浆样本。通过串联质谱分析艾瑞布林的浓度:结果:7 名研究参与者的 12 个脑内微透析导管的透析液样本被纳入分析。在统计学上观察到,BBB受损与完好的脑组织中的麦角苷浓度存在显著差异,平均最大浓度的对数值相差3.37(std err = 0.59,p值 = 0.005)。尽管如此,大脑与血浆中的艾瑞布林总体比率仅为 0.13% 至 1.99%:结论:尽管我们可以在BBB被破坏的脑组织中检测到较高浓度的艾瑞布林,但脑内艾瑞布林水平不足以预测艾瑞布林对脑内肿瘤具有一致的临床意义:Gov 标识符:NCT02338037(2015年1月9日)。
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引用次数: 0
Retraction Note: NO donor inhibits proliferation and induces apoptosis by targeting PI3K/AKT/mTOR and MEK/ERK pathways in hepatocellular carcinoma cells. 撤稿说明:NO 供体通过靶向肝癌细胞中的 PI3K/AKT/mTOR 和 MEK/ERK 通路,抑制细胞增殖并诱导细胞凋亡。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-16 DOI: 10.1007/s00280-024-04718-9
Ling Liu, Jingjing Chen, Mengyao Cao, Jiangang Wang, Shuying Wang
{"title":"Retraction Note: NO donor inhibits proliferation and induces apoptosis by targeting PI3K/AKT/mTOR and MEK/ERK pathways in hepatocellular carcinoma cells.","authors":"Ling Liu, Jingjing Chen, Mengyao Cao, Jiangang Wang, Shuying Wang","doi":"10.1007/s00280-024-04718-9","DOIUrl":"https://doi.org/10.1007/s00280-024-04718-9","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Cancer Chemotherapy and Pharmacology
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