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A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1007/s00280-024-04742-9
Keri R Maher, Danielle Shafer, Dale Schaar, Dipankar Bandyopadhyay, Xiaoyan Deng, John Wright, Richard Piekarz, Michelle A Rudek, R Donald Harvey, Steven Grant

Purpose: Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells. Here, we present the safety, pharmacokinetics and pharmacodynamics of belinostat and pevonedistat in a dose escalation Phase I study in AML and High-Risk MDS.

Methods: Eighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800-1000 mg/m2, pevonedistat 20-50 mg/m2). Safety and tolerability were assessed according to protocol defined dose limiting toxicities (DLTs). Correlative pharmacokinetic and pharmacodynamic analyses were performed.

Results: No dose limiting toxicities were noted. Most Grade 3 or 4 toxicities were hematologic in nature. The best response was stable disease in four patients, and complete remission in one patient who qualified as an exceptional responder. Pharmakokinetic studies revealed no association between drug exposure and best response. Pharmacodynamic RT-PCR studies demonstrated post-treatment increases in several proteins, including quantitative increases in the oxidative stress protein NQO1, ferroptosis protein SLC7A11, and GSR, linked to glutathione metabolism and oxidative stress, as did the anti-oxidants SRXN1 and TXNRD1.

Conclusions: Patterns of post-treatment changes in correlative pharmacodynamic parameters may suggest possible mechanistic changes in the DNA damage response, oxidative damage, and ferroptosis pathways. The combination of pevonedistat plus belinosat is safe in an adult relapsed and/or refractory AML/High-Risk MDS population with modest but notable activity in this heavily treated, high risk population. Our findings also raise the possibility that certain extremely poor prognosis AML patients may respond to a regimen combining two targeted agents that have little or no activity when administered individually.

Trial registration: ClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246.

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引用次数: 0
Pharmacokinetic exposure and treatment outcomes of lenvatinib in patients with renal cell carcinoma and differentiated thyroid carcinoma. lenvatinib在肾细胞癌和分化型甲状腺癌患者中的药代动力学暴露和治疗效果。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1007/s00280-024-04746-5
Marinda Meertens, Eline L Giraud, Esbar Hassan, Sybrand W J Zielhuis, Tiemen T Snels, Ingrid M E Desar, Janneke E W Walraven, Sofie Wilgenhof, Johannes V van Thienen, Jan Paul de Boer, Neeltje Steeghs, Nielka P van Erp, Alwin D R Huitema

Purpose: After initial approval of lenvatinib for radioiodine-refractory differentiated thyroid cancer (DTC), it has also shown promising outcomes in among others metastatic renal cell carcinoma (mRCC). Given that trial populations typically do not represent routine clinical care populations, questions arise about how applicable trial outcomes are in clinical practice. This study aims to compare the pharmacokinetics (PK), toxicity patterns, and survival data of lenvatinib in a real-world cohort with DTC and mRCC to those observed in pivotal clinical trials.

Materials and methods: Patients were included when diagnosed with DTC or mRCC, had received current or prior treatment with lenvatinib, and had at least one available lenvatinib plasma concentration measurement. A descriptive comparison was made between the baseline characteristics, PK data, toxicity and survival data in this real-world cohort and those described in the phase III trials.

Results: Overall, 29 patients with mRCC and 35 patients with DTC were included. For mRCC, median time to treatment discontinuation (mTTD) was shorter than observed in the phase III trial (7.5 versus 11.0 months) with fewer dose-limiting toxicities, likely because 66% of the patients started with a reduced dose. mRCC patients were more pretreated and had a worse performance status than trial participants. This was resembled in overall lower PK exposure in mRCC patients. For DTC, mTTD was longer in our cohort (17.1 versus 13.8 months), with similar toxicity patterns and PK exposure as in the phase III trial.

Conclusions: Our data suggests that patient characteristics and outcomes in routine clinical care deviate from clinical trials and show the need for alternative treatment strategies to manage tolerability to lenvatinib.

目的:lenvatinib最初被批准用于治疗放射性碘难治性分化甲状腺癌(DTC),在其他转移性肾细胞癌(mRCC)中也显示出有希望的结果。鉴于试验人群通常不代表常规临床护理人群,关于试验结果在临床实践中如何适用的问题就出现了。本研究旨在比较lenvatinib在现实世界DTC和mRCC队列中的药代动力学(PK)、毒性模式和生存数据与关键临床试验中观察到的数据。材料和方法:纳入诊断为DTC或mRCC的患者,目前或以前接受过lenvatinib治疗,并且至少有一个可用的lenvatinib血浆浓度测量。将真实世界队列中的基线特征、PK数据、毒性和生存数据与III期试验中描述的数据进行描述性比较。结果:共纳入29例mRCC患者和35例DTC患者。对于mRCC,中位停药时间(mTTD)比III期试验中观察到的短(7.5个月对11.0个月),剂量限制性毒性更少,可能是因为66%的患者开始时剂量减少。mRCC患者比试验参与者有更多的预处理和更差的表现状态。这与mRCC患者总体较低的PK暴露相似。对于DTC,我们的队列中mTTD时间更长(17.1个月对13.8个月),毒性模式和PK暴露与III期试验相似。结论:我们的数据表明,常规临床护理的患者特征和结果偏离临床试验,表明需要替代治疗策略来管理对lenvatinib的耐受性。
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引用次数: 0
Targeting on the PI3K/mTOR: a potential treatment strategy for clear cell ovarian carcinoma. 靶向PI3K/mTOR:透明细胞卵巢癌的潜在治疗策略
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-10 DOI: 10.1007/s00280-024-04748-3
Kewei Zheng, Guanqin Jin, Rui Cao, Yi Gao, Jing Xu, Ranran Chai, Yu Kang

Purpose: Ovarian clear cell carcinoma is a highly malignant gynecological tumor characterized by a high rate of chemotherapy resistance and poor prognosis. The PI3K/AKT/mTOR pathway is well-known to be closely related to the progression of various malignancies, and recent studies have indicated that this pathway may play a critical role in the progression and worsening of OCCC.

Methods: In this study, we investigated the combined effects of WX390, a dual inhibitor of PI3K/mTOR, and cisplatin on OCCC through both in vitro and in vivo experiments to further elucidate their therapeutic effects.

Results: WX390 significantly inhibited the proliferation of human OCCC cell lines ES2 and OVISE, while promoting apoptosis. Furthermore, the combination of WX390 with CDDP exhibited a synergistic effect, markedly increasing the sensitivity of OCCC cells to chemotherapeutic agents and significantly suppressing tumor growth in PDX models. Western blot and RNA-seq analyses revealed that WX390 robustly inhibited the PI3K/AKT/mTOR pathway, interrupt autophagy, altered cell cycle dynamics, and induced apoptosis.

Conclusion: This study comprehensively assessed the efficacy of WX390 across multiple models of OCCC, laying a solid foundation for the development of new therapeutic strategies for this challenging malignancy.

目的:卵巢透明细胞癌是一种化疗耐药率高、预后差的妇科高度恶性肿瘤。众所周知,PI3K/AKT/mTOR通路与各种恶性肿瘤的进展密切相关,最近的研究表明,该通路可能在OCCC的进展和恶化中发挥关键作用。方法:本研究通过体外和体内实验,研究PI3K/mTOR双抑制剂WX390与顺铂联合治疗OCCC的作用,进一步阐明其治疗效果。结果:WX390显著抑制人OCCC细胞株ES2和OVISE的增殖,促进细胞凋亡。此外,WX390与CDDP联合使用具有协同作用,可显著提高OCCC细胞对化疗药物的敏感性,并显著抑制PDX模型中的肿瘤生长。Western blot和RNA-seq分析显示,WX390显著抑制PI3K/AKT/mTOR通路,阻断自噬,改变细胞周期动力学,诱导细胞凋亡。结论:本研究全面评估了WX390在多种OCCC模型中的疗效,为开发新的OCCC治疗策略奠定了坚实的基础。
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引用次数: 0
Endoglin as a predictive biomarker for pemetrexed sensitivity in non-small-cell lung cancer: a cellular study. 内啡肽作为非小细胞肺癌培美曲塞敏感性的预测性生物标志物:一项细胞研究。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-10 DOI: 10.1007/s00280-024-04734-9
Ching-Yuan Cheng, Wen-Chen Chuang, Ching-Pin Lin, Che-Hsing Li, Hui-Yi Chang, Wen-Jun Wu, Ming-Fang Wu, Jiunn-Liang Ko

Objective: Based on our previous research, which demonstrated that elevated plasma endoglin (ENG) levels in lung cancer patients were associated with a better prognosis, increased sensitivity to pemetrexed, and enhanced tumor suppression, this study aims to validate these findings at the cellular level. The focus is on membrane and extracellular ENG and their influence on drug response and tumor cell behavior in non-small cell lung cancer (NSCLC) cells.

Methods: The correlation between ENG expression and pemetrexed-induced cytotoxicity in eight human non-squamous subtype NSCLC cell lines was analyzed. ENG in A549 and H1975 cells was knocked down using shRNA. MTT assay, cell cycle assay, western blot analysis, and boyden chamber assay were used to detect the effect of ENG on pemetrexed-induced cytotoxicity, cell cycle distribution, and cell migration.

Results: The expression of membrane ENG was positively correlated with pemetrexed-induced cytotoxicity in human NSCLC cells. Compared to pemetrexed-sensitive A549 cells, the A549/a400 (pemetrexed-resistant subline) cells exhibited a reduced accumulation of cells in the S phase, making them less susceptible to cell death. ENG knockdown also alleviated pemetrexed-induced S phase arrest and regulated G1/S phase-related proteins (p53, p21, CDK2, and Cyclin A). Additionally, co-treatment with recombinant ENG enhanced pemetrexed-induced migration inhibition in the sensitive cel1 line and cytotoxicity in the resistance cell line.

Conclusion: The present results strengthened our prior clinical findings, showing that higher membrane ENG expression enhances pemetrexed-induced cytotoxicity and S phase arrest, which may involve the ENG-p21 pathway. Additionally, microenvironmental ENG enhanced the anti-migration of pemetrexed. These findings highlight the potential of ENG as a biomarker and therapeutic target, opening new avenues to improve the outcomes of non-squamous cell NSCLC treatment.

目的:基于我们之前的研究,肺癌患者血浆内啡肽(ENG)水平升高与更好的预后、培美曲塞敏感性增加和肿瘤抑制增强相关,本研究旨在从细胞水平验证这些发现。重点关注非小细胞肺癌(NSCLC)细胞的膜和细胞外ENG及其对药物反应和肿瘤细胞行为的影响。方法:分析8种人非鳞状亚型NSCLC细胞ENG表达与培美曲塞诱导的细胞毒性的关系。用shRNA敲除A549和H1975细胞的ENG。采用MTT法、细胞周期法、western blot法和boyden室法检测ENG对培美曲塞诱导的细胞毒性、细胞周期分布和细胞迁移的影响。结果:在人NSCLC细胞中,膜ENG的表达与培美曲塞诱导的细胞毒性呈正相关。与培美曲塞敏感的A549细胞相比,A549/a400(培美曲塞耐药亚系)细胞在S期的细胞积累减少,使其对细胞死亡的易感性降低。ENG敲低也减轻了培美曲塞诱导的S期阻滞和调节G1/S期相关蛋白(p53, p21, CDK2和Cyclin A)。此外,与重组ENG共同处理增强了培美曲塞诱导的敏感细胞系的迁移抑制和抗性细胞系的细胞毒性。结论:本研究结果加强了我们之前的临床发现,表明较高的膜ENG表达增强了培美曲塞诱导的细胞毒性和S期阻滞,这可能涉及ENG-p21途径。微环境ENG增强培美曲塞的抗迁移能力。这些发现突出了ENG作为生物标志物和治疗靶点的潜力,为改善非鳞状细胞NSCLC的治疗结果开辟了新的途径。
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引用次数: 0
Pharmacokinetics, mass balance, and metabolism of [14C]PLB1004, a selective and irreversible EGFR-TKI in humans. 选择性和不可逆EGFR-TKI [14C]PLB1004在人体内的药代动力学、质量平衡和代谢
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-07 DOI: 10.1007/s00280-024-04744-7
Donghui Liu, Qian Li, Shu Yan, Xinyue Zhang, Weiqiang Li, Feiyu Wang, Lei Gao, Fei Geng, Haiyan Zhou, Panpan Ye, Furong Zhao, Weizhe Xue, Peilong Zhang, Xingxing Diao, Wei Zhao

Purpose: PLB1004, developed by Beijing Avistone Biotechnology Co., Ltd., is a safe, highly selective, and efficient irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) employed in treating non-small-cell-lung-cancer (NSCLC). This study investigated its pharmacokinetics, mass balance, and metabolism in 6 healthy Chinese male subjects treated with 160 mg (70 µCi) [14C]PLB1004.

Methods: Following drug administration, samples of blood, urine and feces were collected for quantitative determination of total radioactivity and metabolites were identified through radioactivity detection coupled with UHPLC-MS/MS.

Results: Following drug administration, the median radioactive Tmax was 4.17 h in plasma, with the average t1/2 of PLB1004-related components in plasma of approximately 54.3 h. Over 264 h post-administration, the average cumulative excretion among the six subjects was 95.01% of the administered dose, with 84.71% and 10.30% excreted in feces and urine, respectively. Nine metabolites were characterized and identified and the parent drug PLB1004 was detected in plasma, urine, and feces. Among these metabolites, M689 was the most prevalent one in plasma, urine, and feces, constituting 25.37% of the total plasma radioactivity, and 55.88% and 1.73% of the administrated dose in feces and urine, respectively.

Conclusion: Fecal excretion emerged as PLB1004 excretion route, while urinary excretion via the kidneys served as the secondary route. The primarily metabolic pathways are oxidation, demethylation, dehydrogenation, and cysteine conjugation in humans.

目的:PLB1004是一种安全、高选择性、高效的不可逆表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),用于治疗非小细胞肺癌(NSCLC)。本研究在6名健康男性受试者中研究了160 mg(70µCi) [14C]PLB1004的药代动力学、质量平衡和代谢。方法:给药后采集血液、尿液和粪便标本,定量测定总放射性,并结合UHPLC-MS/MS检测代谢产物。结果:给药后,血浆中放射性Tmax中位数为4.17 h,血浆中plb1004相关成分的t1/2平均约为54.3 h。给药264 h后,6名受试者的平均累积排泄量为给药剂量的95.01%,粪便和尿液中分别为84.71%和10.30%。对9种代谢物进行了表征和鉴定,并在血浆、尿液和粪便中检测到母体药物PLB1004。其中,M689在血浆、尿液和粪便中含量最高,占血浆总放射性的25.37%,粪便和尿液中分别占给药剂量的55.88%和1.73%。结论:粪便排泄是PLB1004的主要排泄途径,肾脏尿路排泄是其次要排泄途径。人体的主要代谢途径是氧化、去甲基化、脱氢和半胱氨酸偶联。
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引用次数: 0
Landscape analysis of adverse events and dose intensity for FDA approved oncology small molecules. FDA批准的肿瘤小分子药物不良事件和剂量强度的景观分析。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-04 DOI: 10.1007/s00280-024-04721-0
Keagan P Collins, Donghua Yin, Yazdi K Pithavala, Rajendar K Mittapalli

As development of new oncology small molecule therapies is focused mainly on molecularly targeted agents, the dose selection paradigm has shifted from the maximum tolerated dose (MTD)-based approach traditionally utilized with cytotoxic drugs towards determining an optimal dose with long-term tolerability while maintaining efficacy. To assess overall tolerability in recently approved oncology small molecules, we surveyed 54 compounds approved by the FDA since March 2017 with respect to dose intensity, dose modifications, and treatment emergent adverse events (TEAEs). Of the 54 new molecular entities surveyed, only 15 were approved at a label dose equal to the MTD (Label Dose = MTD). Compared to compounds where the label dose was less than the MTD, compounds where the Label Dose = MTD reported overall lower dose intensity and higher dose modifications due to adverse events, though treatment discontinuations due to adverse events were similar. A post-marketing requirement (PMR) for dose optimization was issued for 7 compounds in the dataset, of which 3 were at the Label Dose = MTD. None of these 7 compounds reported a positive exposure-response relationship in efficacy and only 4 reported an exposure-response in safety events. Overall, dose intensity was lower, and incidence of dose modifications, discontinuations, and Grade ≥ 3 TEAEs were higher in compounds issued a PMR vs. the latter. This analysis suggests that while recently approved oncology small molecules have a reasonable relative dose intensity (RDI), the higher incidence of Grade ≥ 3 TEAEs and dose modifications where Label Dose = MTD highlight the continuing need for dose optimization while developing oncology therapeutics.

随着新的肿瘤小分子疗法的发展主要集中在分子靶向药物上,剂量选择范式已经从传统上用于细胞毒性药物的基于最大耐受剂量(MTD)的方法转向确定长期耐受性同时保持疗效的最佳剂量。为了评估最近批准的肿瘤小分子的总体耐受性,我们调查了自2017年3月以来FDA批准的54种化合物的剂量强度、剂量修改和治疗紧急不良事件(teae)。在被调查的54个新分子实体中,只有15个被批准的标签剂量等于MTD(标签剂量= MTD)。与标签剂量小于MTD的化合物相比,标签剂量= MTD的化合物报告的总体剂量强度较低,由于不良事件引起的剂量调整较高,尽管由于不良事件导致的治疗中断相似。针对数据集中的7种化合物发布了剂量优化上市后要求(PMR),其中3种为标签剂量= MTD。这7种化合物中没有一种在疗效上报告了正的暴露-反应关系,只有4种在安全性事件中报告了暴露-反应。总的来说,与后者相比,获得PMR的化合物的剂量强度更低,剂量调整、停药和≥3级teae的发生率更高。该分析表明,虽然最近批准的肿瘤小分子具有合理的相对剂量强度(RDI),但≥3级teae的较高发生率和标签剂量= MTD的剂量修改突出了在开发肿瘤治疗方法时继续需要剂量优化。
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引用次数: 0
Nanotechnology and nanobots unleashed: pioneering a new era in gynecological cancer management - a comprehensive review. 纳米技术和纳米机器人释放:开创妇科癌症管理的新时代-全面回顾。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-04 DOI: 10.1007/s00280-024-04747-4
Naina Kumar, Mishu Mangla

Introduction: Gynecological cancers, such as ovarian, cervical, and endometrial malignancies, are notoriously challenging due to their intricate biology and the critical need for precise diagnostic and therapeutic approaches. In recent years, groundbreaking advances in nanotechnology and nanobots have emerged as game-changers in this arena, offering the promise of a new paradigm in cancer management. This comprehensive review delves into the revolutionary potential of these technologies, showcasing their ability to transform the landscape of gynecological oncology.

Methodology: A systematic literature search spanning from March 2005 to August 2024 was conducted using major databases such as PubMed, Google Scholar, and Scopus. Keywords included "nanotechnology," "nanobots," "gynecological cancers," "ovarian cancer," "cervical cancer," and "endometrial cancer." Relevant articles published in English were selected based on their focus on nanotechnology and nanobots in the diagnosis, treatment, and management of gynecological cancers. The findings were synthesized to present a coherent overview of how nanotechnology and nanobots are reshaping gynecological cancer management. The review highlights key innovations, current applications, and future directions for research and clinical implementation.

Conclusion: The integration of nanotechnology and nanobots in gynecological cancer management represents a groundbreaking shift in the field. Recent advancements in nanoscale materials and robotic technology offer unprecedented opportunities for precision diagnosis, targeted drug delivery, and innovative therapeutic approaches. Despite promising developments, challenges such as biocompatibility, safety, and regulatory issues remain. Continued research and clinical trials are essential to overcome these hurdles and fully realize the potential of nanotechnology and nanobots.

妇科癌症,如卵巢癌、宫颈癌和子宫内膜恶性肿瘤,由于其复杂的生物学和对精确诊断和治疗方法的迫切需要,是众所周知的具有挑战性的。近年来,纳米技术和纳米机器人的突破性进展已经成为这一领域的游戏规则改变者,为癌症管理提供了新的范例。这篇全面的综述深入研究了这些技术的革命性潜力,展示了它们改变妇科肿瘤学景观的能力。方法:利用PubMed、b谷歌Scholar、Scopus等主要数据库对2005年3月至2024年8月的文献进行系统检索。关键词包括“纳米技术”、“纳米机器人”、“妇科癌症”、“卵巢癌”、“宫颈癌”和“子宫内膜癌”。根据纳米技术和纳米机器人在妇科癌症的诊断、治疗和管理方面的重点,选择了相关的英文论文。综合这些发现,对纳米技术和纳米机器人如何重塑妇科癌症管理进行了连贯的概述。这篇综述强调了关键的创新、当前的应用以及未来的研究和临床实施方向。结论:纳米技术和纳米机器人在妇科肿瘤治疗中的应用代表了该领域的突破性转变。纳米材料和机器人技术的最新进展为精确诊断、靶向给药和创新治疗方法提供了前所未有的机会。尽管前景看好,但生物相容性、安全性和监管问题等挑战依然存在。持续的研究和临床试验对于克服这些障碍和充分实现纳米技术和纳米机器人的潜力至关重要。
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引用次数: 0
DPYD genotype should be extended to rare variants: report on two cases of phenotype / genotype discrepancy. DPYD基因型应扩展到罕见变异:报告两例表型/基因型差异。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-01-02 DOI: 10.1007/s00280-024-04738-5
Paul Vilquin, Yves Medard, Fabienne Thomas, Lauriane Goldwirt, Luis Teixeira, Samia Mourah, Evelyne Jacqz-Aigrain

The enzyme dihydropyrimidine dehydrogenase (DPD) is the primary catabolic pathway of fluoropyrimidines including 5 fluorouracil (5FU) and capecitabine. Cases of lethal toxicity have been reported in cancer patients with complete DPD deficiency receiving standard dose of 5FU or capecitabine. DPD is encoded by the pharmacogene DPYD in which more than 200 variants have been identified. Different approaches have been developed for screening DPD-deficiency, including DPYD genotyping and phenotyping. Plasma uracil ([U]) and dihydrouracil ([UH2]) concentrations are routinely used as surrogate markers for systemic DPD activity: [U] ≥ 16 ng/ml and < 150 ng/ml, and [U] ≥ 150 ng/mL indicate partial and complete DPD deficient phenotype, respectively, while values of 5 or 10 for [UH2]/([U] ratio are often cited. Four clinically relevant DPYD defective variants (DPYD*13, DPYD*2A, p.Asp949Val and haplotype B3), are targeted in genetic testing via PCR. In practice, pretreatment [U], alone or combined with these 4 recommended DPYD alleles guides individual dosage selection, though this approach has limitations. This is illustrated by two cases showing discrepancy between DPD deficient phenotype and normal standard genotype. In these two cases, DPYD exome sequencing with Next Generation Sequencing identified rare inactive variants, establishing concordance between phenotype and genotype. In patient 1, [U] levels of 21.1 and 25.5 ng/mL, indicated partial deficiency though the targeted genotype was normal and 5FU dose was adjusted based on the phenotype. In patient 2, [U] levels of 16.2 and 15.2 ng/mL were near the 16 ng/ml threshold. With a normal genotype, he as considered non-deficient as targeted genotype was normal and the standard dose was administered. These two cases underscore the need to pair DPD phenotyping with whole DPYD gene sequencing, due to the frequent discrepancies between these pharmacogenetic tools, the burden of rare variants and ethnic differences in variant frequencies.

二氢嘧啶脱氢酶(DPD)是包括5氟尿嘧啶(5FU)和卡培他滨在内的氟嘧啶的主要分解代谢途径。在接受标准剂量的5FU或卡培他滨治疗的完全DPD缺乏症癌症患者中有致死毒性的报道。DPD由药物基因DPYD编码,其中已有200多种变体被发现。不同的方法已经开发用于筛选DPYD缺乏症,包括DPYD基因分型和表型分型。血浆尿嘧啶([U])和二氢尿嘧啶([UH2])浓度通常被用作全身DPD活性的替代标记物:[U]≥16 ng/ml和
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引用次数: 0
Tenuigenin inhibits osteosarcoma growth via CIP2A/PP2A/NF-κB axis. 黄芪黄素通过CIP2A/PP2A/NF-κB轴抑制骨肉瘤生长。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-12-30 DOI: 10.1007/s00280-024-04733-w
Shuo Yang, Shasha Liu, Zixun Dai

Background: Polygala tenuifolia and its active components have been revealed to possess anti-tumor activities. However, the role of Tenuigenin (TEN), a bioactive ingredient from Polygala tenuifolia, in tumors such as osteosarcoma (OS) remains unclear. The present research intended to explore the efficacy and underlying mechanism of TEN on OS.

Methods: OS cells were administrated with different concentrations of TEN. Cell viability, proliferation, invasion, and migration were assessed with CCK-8 assay, colony formation assay, transwell assay, and wound healing assay, respectively. Protein and mRNA levels were determined with western blot and qRT-PCR, while protein phosphatase 2A (PP2A) activity was tested with PP2A phosphatase assay kit. The interaction between PP2A and cancerous inhibitor of protein phosphatase 2A (CIP2A) or nuclear factor kappaB (NF-κB) signaling was detected using co-immunoprecipitation. p-p65 expression in the nucleus was determined with immunofluorescence. The efficacy of TEN in vivo was also explored in a xenograft tumor model. Immunohistochemistry was performed to detect CIP2A and Ki67 in mice.

Results: TEN treatment or CIP2A depletion repressed cell viability, proliferation, invasion, and migration in OS cells. Additionally, TEN reduced CIP2A, increased PP2A activity, and inactivated NF-κB signaling. PP2A directly interacted with CIP2A or NF-κB signaling, and PP2A inhibition reversed CIP2A knockdown-induced repression of NF-κB signaling. CIP2A overexpression overturned the efficacy of TEN, which was reversed by NF-κB inhibition. TEN decreased CIP2A, elevated PP2A activity, inactivated NF-κB signaling, and inhibited tumor growth in vivo, which was antagonized by CIP2A overexpression.

Conclusion: TEN suppressed OS growth via CIP2A/PP2A/NF-κB axis, indicating that it would be a novel drug for treating OS.

背景:荆芥及其有效成分已被证实具有抗肿瘤活性。然而,Tenuigenin (TEN)是一种来自tenuifolia的生物活性成分,其在骨肉瘤(OS)等肿瘤中的作用尚不清楚。本研究旨在探讨TEN对OS的疗效及其机制。方法:用不同浓度的TEN给药于OS细胞。分别用CCK-8法、菌落形成法、transwell法和伤口愈合法评估细胞活力、增殖、侵袭和迁移。western blot和qRT-PCR检测蛋白和mRNA水平,PP2A磷酸酶检测试剂盒检测蛋白磷酸酶2A (PP2A)活性。采用共免疫沉淀法检测PP2A与蛋白磷酸酶2A (CIP2A)癌性抑制剂或核因子κ b (NF-κB)信号的相互作用。免疫荧光法检测细胞核中P-p65的表达。在异种移植肿瘤模型中也探讨了TEN在体内的疗效。免疫组化检测小鼠CIP2A和Ki67。结果:TEN处理或CIP2A缺失抑制了OS细胞的活力、增殖、侵袭和迁移。此外,TEN降低CIP2A,增加PP2A活性,并使NF-κB信号失活。PP2A直接与CIP2A或NF-κB信号相互作用,PP2A抑制逆转了CIP2A敲低诱导的NF-κB信号抑制。CIP2A过表达推翻了TEN的疗效,而这一作用被NF-κB抑制所逆转。TEN在体内降低CIP2A,提高PP2A活性,使NF-κB信号失活,抑制肿瘤生长,其作用被CIP2A过表达拮抗。结论:TEN通过CIP2A/PP2A/NF-κB轴抑制OS生长,有望成为治疗OS的新型药物。
{"title":"Tenuigenin inhibits osteosarcoma growth via CIP2A/PP2A/NF-κB axis.","authors":"Shuo Yang, Shasha Liu, Zixun Dai","doi":"10.1007/s00280-024-04733-w","DOIUrl":"https://doi.org/10.1007/s00280-024-04733-w","url":null,"abstract":"<p><strong>Background: </strong>Polygala tenuifolia and its active components have been revealed to possess anti-tumor activities. However, the role of Tenuigenin (TEN), a bioactive ingredient from Polygala tenuifolia, in tumors such as osteosarcoma (OS) remains unclear. The present research intended to explore the efficacy and underlying mechanism of TEN on OS.</p><p><strong>Methods: </strong>OS cells were administrated with different concentrations of TEN. Cell viability, proliferation, invasion, and migration were assessed with CCK-8 assay, colony formation assay, transwell assay, and wound healing assay, respectively. Protein and mRNA levels were determined with western blot and qRT-PCR, while protein phosphatase 2A (PP2A) activity was tested with PP2A phosphatase assay kit. The interaction between PP2A and cancerous inhibitor of protein phosphatase 2A (CIP2A) or nuclear factor kappaB (NF-κB) signaling was detected using co-immunoprecipitation. p-p65 expression in the nucleus was determined with immunofluorescence. The efficacy of TEN in vivo was also explored in a xenograft tumor model. Immunohistochemistry was performed to detect CIP2A and Ki67 in mice.</p><p><strong>Results: </strong>TEN treatment or CIP2A depletion repressed cell viability, proliferation, invasion, and migration in OS cells. Additionally, TEN reduced CIP2A, increased PP2A activity, and inactivated NF-κB signaling. PP2A directly interacted with CIP2A or NF-κB signaling, and PP2A inhibition reversed CIP2A knockdown-induced repression of NF-κB signaling. CIP2A overexpression overturned the efficacy of TEN, which was reversed by NF-κB inhibition. TEN decreased CIP2A, elevated PP2A activity, inactivated NF-κB signaling, and inhibited tumor growth in vivo, which was antagonized by CIP2A overexpression.</p><p><strong>Conclusion: </strong>TEN suppressed OS growth via CIP2A/PP2A/NF-κB axis, indicating that it would be a novel drug for treating OS.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"15"},"PeriodicalIF":2.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909415","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
Variations in serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment. 长期接受舒尼替尼治疗的患者血清舒尼替尼及其代谢物浓度的变化
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-12-26 DOI: 10.1007/s00280-024-04741-w
Miki Takenaka Sato, Takuya Araki, Hideaki Yashima, Yuya Ishikawa, Jun Morita, Yoshiko Maeda, Masayuki Ohbayashi, Noriko Kohyama, Yoshio Ogawa, Takashi Fukagai, Koujirou Yamamoto, Mari Kogo

Purpose: The blood concentrations of some tyrosine kinase inhibitors are known to decrease with long-term administration. We evaluated the variability in the serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment.

Methods: This study prospectively recruited patients who received sunitinib for metastatic renal cell carcinoma at the Showa University Hospital between March 2020 and January 2022. Bivariate correlations between the serum concentration/dose (C/D) ratios of sunitinib and its metabolites (i.e., N-desethyl sunitinib and sunitinib N-oxide) and treatment duration were evaluated using Pearson's correlation coefficient.

Results: Seven patients were enrolled, and 79 blood samples were collected. Among six patients who received sunitinib for > 1 year, three showed a decreasing trend in the C/D ratio of sunitinib (Pt1: r = -0.608, p = 0.047; Pt2: r = -0.555, p = 0.077; Pt6: r = -0.590, p = 0.073). In these patients, the median annual decrease in the C/D ratio of sunitinib was 55.8% (26.5-63.2%). Additionally, two of the three patients also showed a decrease in the C/D ratio of N-desethyl sunitinib. The ratio of N-desethyl sunitinib/sunitinib concentration at baseline and the end of follow-up was similar between the C/D-decreased and C/D-non-decreased groups.

Conclusion: This study showed that the C/D ratio of sunitinib decreased by half over time in half of the patients who received long-term sunitinib treatment despite continuing the same dose. Therefore, serum concentrations of sunitinib and its metabolites should be monitored periodically in patients receiving long-term treatment to prevent decrease in serum sunitinib concentrations.

目的:已知一些酪氨酸激酶抑制剂的血药浓度随长期服用而降低。我们评估了长期接受舒尼替尼治疗的患者血清舒尼替尼及其代谢物浓度的变异性。方法:本研究前瞻性招募2020年3月至2022年1月在昭和大学医院接受舒尼替治疗转移性肾细胞癌的患者。使用Pearson相关系数评估舒尼替尼及其代谢物(即n -去乙基舒尼替尼和n -氧化舒尼替尼)的血清浓度/剂量(C/D)比与治疗时间之间的双变量相关性。结果:共纳入7例患者,采集血样79份。在接受舒尼替尼治疗10年的6例患者中,有3例患者舒尼替尼的C/D比呈下降趋势(Pt1: r = -0.608, p = 0.047;Pt2: r = -0.555, p = 0.077;Pt6: r = -0.590, p = 0.073)。在这些患者中,舒尼替尼的C/D比率的年中位数下降为55.8%(26.5-63.2%)。此外,3例患者中有2例也显示n -去乙基舒尼替尼的C/D比降低。基线和随访结束时n-去乙基舒尼替尼/舒尼替尼浓度之比在C/ d减少组和C/ d未减少组之间相似。结论:本研究显示,在接受长期舒尼替尼治疗的一半患者中,尽管继续使用相同剂量,但随着时间的推移,舒尼替尼的C/D比率下降了一半。因此,长期接受治疗的患者应定期监测舒尼替尼及其代谢物的血清浓度,以防止舒尼替尼血清浓度下降。
{"title":"Variations in serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment.","authors":"Miki Takenaka Sato, Takuya Araki, Hideaki Yashima, Yuya Ishikawa, Jun Morita, Yoshiko Maeda, Masayuki Ohbayashi, Noriko Kohyama, Yoshio Ogawa, Takashi Fukagai, Koujirou Yamamoto, Mari Kogo","doi":"10.1007/s00280-024-04741-w","DOIUrl":"10.1007/s00280-024-04741-w","url":null,"abstract":"<p><strong>Purpose: </strong>The blood concentrations of some tyrosine kinase inhibitors are known to decrease with long-term administration. We evaluated the variability in the serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment.</p><p><strong>Methods: </strong>This study prospectively recruited patients who received sunitinib for metastatic renal cell carcinoma at the Showa University Hospital between March 2020 and January 2022. Bivariate correlations between the serum concentration/dose (C/D) ratios of sunitinib and its metabolites (i.e., N-desethyl sunitinib and sunitinib N-oxide) and treatment duration were evaluated using Pearson's correlation coefficient.</p><p><strong>Results: </strong>Seven patients were enrolled, and 79 blood samples were collected. Among six patients who received sunitinib for > 1 year, three showed a decreasing trend in the C/D ratio of sunitinib (Pt1: r = -0.608, p = 0.047; Pt2: r = -0.555, p = 0.077; Pt6: r = -0.590, p = 0.073). In these patients, the median annual decrease in the C/D ratio of sunitinib was 55.8% (26.5-63.2%). Additionally, two of the three patients also showed a decrease in the C/D ratio of N-desethyl sunitinib. The ratio of N-desethyl sunitinib/sunitinib concentration at baseline and the end of follow-up was similar between the C/D-decreased and C/D-non-decreased groups.</p><p><strong>Conclusion: </strong>This study showed that the C/D ratio of sunitinib decreased by half over time in half of the patients who received long-term sunitinib treatment despite continuing the same dose. Therefore, serum concentrations of sunitinib and its metabolites should be monitored periodically in patients receiving long-term treatment to prevent decrease in serum sunitinib concentrations.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"14"},"PeriodicalIF":2.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892407","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
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Cancer Chemotherapy and Pharmacology
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