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Inhibition of proteinase-activated receptor 2 (PAR2) decreased the malignant progression of lung cancer cells and increased the sensitivity to chemotherapy. 抑制蛋白酶激活受体 2(PAR2)可减少肺癌细胞的恶性进展,并提高对化疗的敏感性。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-01-04 DOI: 10.1007/s00280-023-04630-8
Hongjie Huo, Yu Feng, Qiong Tang

Objectives: This study aimed to study the effect of protease-activated receptor 2 (PAR2) on the proliferation, invasion, and clone formation of lung cancer cells. It also aimed to evaluate the inhibitory effect of melittin on PAR2 and the anti-lung cancer effect of melittin combined with gefitinib.

Methods: The correlation between the co-expression of PAR2 and epithelial-mesenchymal transition (EMT) markers was analyzed. PAR2 in A549 and NCI-H1299 cells was knocked down using siRNA. MTT assay, Transwell assay, and colony formation assay were used to detect the effects of PAR2 on cell proliferation, invasion, and clone formation. The anti-cancer effect of PAR2 knockdown on gefitinib treatment was analyzed. The synergistic effect of melittin on gefitinib treatment by inhibiting PAR2 and the underlying molecular mechanism were further analyzed and tested.

Results: The expression of PAR2 was upregulated in lung cancer, which was associated with the poor prognosis of lung cancer. PAR2 knockdown inhibited the stemness and EMT of lung cancer cells. It also inhibited the proliferation, invasion, and colony formation of A549 and NCI-H1299 cells. Moreover, PAR2 knockdown increased the chemotherapeutic sensitivity of gefitinib in lung cancer. Melittin inhibited PAR2 and the malignant progression of lung cancer cells. Melittin increased the chemotherapeutic sensitivity of gefitinib in lung cancer by inhibiting PAR2.

Conclusion: PAR2 may promote the proliferation, invasion, and colony formation of lung cancer cells by promoting EMT. Patients with a high expression of PAR2 have a poor prognosis. Inhibition of PAR2 increased the chemotherapeutic sensitivity of gefitinib. PAR2 may be a potential therapeutic target and diagnostic marker for lung cancer.

研究目的本研究旨在探讨蛋白酶激活受体2(PAR2)对肺癌细胞增殖、侵袭和克隆形成的影响。还旨在评估美利汀对 PAR2 的抑制作用以及美利汀联合吉非替尼的抗肺癌作用:方法:分析了 PAR2 与上皮-间质转化(EMT)标志物共表达之间的相关性。使用 siRNA 敲除 A549 和 NCI-H1299 细胞中的 PAR2。MTT试验、Transwell试验和集落形成试验用于检测PAR2对细胞增殖、侵袭和克隆形成的影响。分析了 PAR2 基因敲除对吉非替尼治疗的抗癌效果。进一步分析和检验了美利汀通过抑制 PAR2 对吉非替尼治疗的协同作用及其分子机制:结果:PAR2在肺癌中表达上调,与肺癌的不良预后有关。结果:PAR2在肺癌中表达上调,这与肺癌预后不良有关。它还能抑制 A549 和 NCI-H1299 细胞的增殖、侵袭和集落形成。此外,PAR2 基因敲除还能提高吉非替尼对肺癌化疗的敏感性。美利汀能抑制 PAR2 和肺癌细胞的恶性进展。通过抑制 PAR2,美利汀提高了吉非替尼对肺癌的化疗敏感性:结论:PAR2可通过促进EMT促进肺癌细胞的增殖、侵袭和集落形成。结论:PAR2 可通过促进 EMT 来促进肺癌细胞的增殖、侵袭和集落形成,PAR2 高表达的患者预后较差。抑制PAR2可增加吉非替尼的化疗敏感性。PAR2 可能是肺癌的潜在治疗靶点和诊断标志物。
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引用次数: 0
Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants. 米哚妥林药物相互作用概况:对健康参与者体内的 CYP3A、CYP2B6 和 CYP2C8 药物底物以及口服避孕药进行全面评估。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-01-25 DOI: 10.1007/s00280-023-04635-3
Romain Sechaud, Helen Gu, Gholamreza Rahmanzadeh, Amanda Taylor, Ovidiu Chiparus, Gopal Krishna Sharma, Astrid Breitschaft, Hans D Menssen

Purpose: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants.

Methods: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2.

Results: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported.

Conclusion: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

目的:米多司林被批准用于治疗FLT-3突变的急性髓性白血病和晚期系统性肥大细胞增多症,它通过细胞色素P450(CYP)3A4代谢为两种主要代谢物,并可能抑制和/或诱导CYP3A、CYP2B6和CYP2C8。有两项研究调查了米哚妥林对CYP底物药物和口服避孕药的影响:方法: 为保证参与者的安全,采用哨点给药法评估了米哚妥林在25天(研究1)或24天(研究2)稳定状态下对CYP底物的影响,在研究1中为咪达唑仑(CYP3A4)、安非他明(CYP2B6)和吡格列酮(CYP2C8);在研究2中为单相口服避孕药(含炔雌醇[EES]和左炔诺孕酮[LVG]):在研究1中,米哚妥林导致咪达唑仑峰值血浆浓度(Cmax)增加10%,总暴露量(AUC)减少3-4%。安非他酮的 Cmax 降低了 55%,AUC 降低了 48-49%。吡格列酮的 Cmax 降低了 10%,AUC 降低了 6%。在研究 2 中,米哚妥林导致 EES 的 Cmax 增加 26%,AUC 增加 7-10%;LVG 的 Cmax 增加 19%,AUC 增加 29-42%。在服用CYP底物药物或口服避孕药时,米哚妥林50毫克,每日两次,连续服用28天,可确保米哚妥林和活性代谢物达到稳态浓度。结论结论:米多司林对 CYP3A4 和 CYP2C8 既无抑制作用,也无诱导作用,对 CYP2B6 的诱导作用较弱。稳定状态下的米哚妥林与激素类避孕药没有临床相关的 PK 相互作用。所有治疗的耐受性都很好。
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引用次数: 0
The landscape of very important pharmacogenes variants and potential clinical relevance in the Chinese Jingpo population: a comparative study with worldwide populations. 中国景颇族人群中非常重要的药物基因变异情况及其潜在的临床意义:一项与全球人群的比较研究。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-02-01 DOI: 10.1007/s00280-023-04638-0
Xiaoya Ma, Yujie Li, Xufeng Zang, Jinping Guo, Wenqian Zhou, Junhui Han, Jing Liang, Panpan Wan, Hua Yang, Tianbo Jin

Background: Pharmacogenomics is a facet of personalized medicine that explores how genetic variants affect drug metabolism and adverse drug reactions. Therefore, this study aims to detect distinct pharmacogenomic variations among the Jingpo population and explore their clinical correlation with drug metabolism and toxicity.

Methods: Agena MassARRAY Assay was used to genotype 57 VIP variants in 28 genes from 159 unrelated Jingpo participants. Subsequently, the chi-squared test and Bonferroni's statistical tests were utilized to conduct a comparative analysis of genotypes and allele frequencies between the Jingpo population and the other 26 populations from the 1000 Genome Project.

Results: We discovered that the KHV (Kinh in Ho ChiMinh City, Vietnam), CHS (Southern Han Chi-nese, China) and JPT (Japanese in Tokyo, Japan) exhibited the smallest differences from the Jingpo with only 4 variants, while ESN (Esan in Nigeria) exhibited the largest differences with 30 variants. Besides, a total of six considerably different loci (rs4291 in ACE, rs20417 in PTGS2, rs1801280 and rs1799929 in NAT2, rs2115819 in ALOX5, rs1065852 in CYP2D6, p < 3.37 × 10-5) were identified in this study. According to PharmGKB, rs20417 (PTGS2), rs4291 (ACE), rs2115819 (ALOX5) and rs1065852 (CYP2D6) were found to be associated with the metabolism efficiency of non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, montelukast and tamoxifen, respectively. Meanwhile, rs1801280 and rs1799929 (NAT2) were found to be related to drug poisoning with slow acetylation.

Conclusion: Our study unveils distinct pharmacogenomic variants in the Jingpo population and discovers their association with the metabolic efficiency of NSAIDs, montelukast, and tamoxifen.

背景:药物基因组学是个性化医疗的一个方面,它探讨基因变异如何影响药物代谢和药物不良反应。因此,本研究旨在检测景颇族人群中不同的药物基因组变异,并探讨其与药物代谢和毒性的临床相关性:方法:使用 Agena MassARRAY 分析法对 159 名无血缘关系的景颇族参与者的 28 个基因中的 57 个 VIP 变异进行基因分型。随后,利用卡方检验(chi-squared test)和邦费罗尼统计检验(Bonferroni's statistical tests)对景颇族人群与千人基因组计划其他 26 个人群的基因型和等位基因频率进行比较分析:我们发现,KHV(越南胡志明市的京族)、CHS(中国南方的汉族池州人)和 JPT(日本东京的日本人)与景颇族的差异最小,只有 4 个变体,而 ESN(尼日利亚的埃桑族)的差异最大,有 30 个变体。此外,本研究还发现了 6 个差异较大的位点(ACE 中的 rs4291、PTGS2 中的 rs20417、NAT2 中的 rs1801280 和 rs1799929、ALOX5 中的 rs2115819、CYP2D6 中的 rs1065852,p -5)。根据PharmGKB,rs20417(PTGS2)、rs4291(ACE)、rs2115819(ALOX5)和rs1065852(CYP2D6)分别与非类固醇抗炎药(NSAIDs)、阿司匹林、孟鲁司特和他莫昔芬的代谢效率有关。同时,rs1801280 和 rs1799929(NAT2)被发现与乙酰化缓慢的药物中毒有关:我们的研究揭示了景颇族人群中不同的药物基因组变异,并发现了它们与非甾体抗炎药、孟鲁司特和他莫昔芬代谢效率的关系。
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引用次数: 0
Visceral obesity and sarcopenia as predictors of efficacy and hematological toxicity in patients with metastatic breast cancer treated with CDK 4/6 inhibitors. 内脏肥胖症和肌肉疏松症是CDK 4/6抑制剂治疗转移性乳腺癌患者疗效和血液毒性的预测因素。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-03-04 DOI: 10.1007/s00280-024-04641-z
Kadriye Bir Yücel, Uguray Aydos, Osman Sütcüoglu, Atiye Cenay Karabörk Kılıç, Nuriye Özdemir, Ahmet Özet, Ozan Yazıcı

Purpose: We aimed to investigate whether visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle area (SMA) index are predictive for efficacy and hematological toxicity in ER + HER2-metastatic breast cancer (BC) patients who received CDK 4/6 inhibitors.

Methods: This retrospective cohort study analyzed 52 patients who were treated with CDK 4/6 inhibitors between January 2018 and February 2021. The values of VAT, SAT, SMA indices and hematological parameters were noted before the start, at the third and sixth months of this treatment. The skeletal muscle area (SMA) and adipose tissue measurements were calculated at the level of the third lumbar vertebra. A SMA-index value of <40 cm2/m2 was accepted as the threshold value for sarcopenia.

Results: Patients with sarcopenia had a worse progression-free survival (PFS) compared to patients without sarcopenia (19.6 vs. 9.0 months, p = 0.005). Patients with a high-VAT-index had a better PFS (20.4 vs. 9.3 months, p = 0.033). Only the baseline low-SMA- index (HR: 3.89; 95% CI: 1.35-11.25, p = 0.012) and baseline low-VAT-index (HR: 2.15; 95% CI: 1.02-4.53, p = 0.042) had significantly related to poor PFS in univariate analyses. The low-SMA-index was the only independent factor associated with poor PFS (HR: 3.99; 95% CI: 1.38-11.54, p = 0.011). No relationship was observed between body composition parameters and grade 3-4 hematological toxicity.

Conclusion: The present study supported the significance of sarcopenia and low visceral adipose tissue as potential early indicators of poor PFS in patients treated with CDK 4/6 inhibitors.

目的:我们旨在研究内脏脂肪组织(VAT)、皮下脂肪组织(SAT)和骨骼肌面积(SMA)指数是否能预测接受CDK 4/6抑制剂治疗的ER + HER2转移性乳腺癌(BC)患者的疗效和血液毒性:这项回顾性队列研究分析了2018年1月至2021年2月期间接受CDK 4/6抑制剂治疗的52名患者。研究人员记录了治疗开始前、治疗第3个月和第6个月的VAT、SAT、SMA指数和血液学参数值。骨骼肌面积(SMA)和脂肪组织的测量值是在第三腰椎水平计算得出的。SMA指数值为2/m2,即为肌肉疏松症的临界值:结果:与无肌少症患者相比,肌少症患者的无进展生存期(PFS)更短(19.6 个月对 9.0 个月,P = 0.005)。高VAT指数患者的无进展生存期更长(20.4个月对9.3个月,p = 0.033)。在单变量分析中,只有基线低SMA指数(HR:3.89;95% CI:1.35-11.25,p = 0.012)和基线低VAT指数(HR:2.15;95% CI:1.02-4.53,p = 0.042)与较差的PFS显著相关。低SMA指数是唯一与不良PFS相关的独立因素(HR:3.99;95% CI:1.38-11.54,P = 0.011)。没有观察到身体成分参数与3-4级血液毒性之间的关系:本研究支持肌肉疏松症和低内脏脂肪组织作为 CDK 4/6 抑制剂治疗患者不良 PFS 潜在早期指标的重要性。
{"title":"Visceral obesity and sarcopenia as predictors of efficacy and hematological toxicity in patients with metastatic breast cancer treated with CDK 4/6 inhibitors.","authors":"Kadriye Bir Yücel, Uguray Aydos, Osman Sütcüoglu, Atiye Cenay Karabörk Kılıç, Nuriye Özdemir, Ahmet Özet, Ozan Yazıcı","doi":"10.1007/s00280-024-04641-z","DOIUrl":"10.1007/s00280-024-04641-z","url":null,"abstract":"<p><strong>Purpose: </strong>We aimed to investigate whether visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle area (SMA) index are predictive for efficacy and hematological toxicity in ER + HER2-metastatic breast cancer (BC) patients who received CDK 4/6 inhibitors.</p><p><strong>Methods: </strong>This retrospective cohort study analyzed 52 patients who were treated with CDK 4/6 inhibitors between January 2018 and February 2021. The values of VAT, SAT, SMA indices and hematological parameters were noted before the start, at the third and sixth months of this treatment. The skeletal muscle area (SMA) and adipose tissue measurements were calculated at the level of the third lumbar vertebra. A SMA-index value of <40 cm<sup>2</sup>/m<sup>2</sup> was accepted as the threshold value for sarcopenia.</p><p><strong>Results: </strong>Patients with sarcopenia had a worse progression-free survival (PFS) compared to patients without sarcopenia (19.6 vs. 9.0 months, p = 0.005). Patients with a high-VAT-index had a better PFS (20.4 vs. 9.3 months, p = 0.033). Only the baseline low-SMA- index (HR: 3.89; 95% CI: 1.35-11.25, p = 0.012) and baseline low-VAT-index (HR: 2.15; 95% CI: 1.02-4.53, p = 0.042) had significantly related to poor PFS in univariate analyses. The low-SMA-index was the only independent factor associated with poor PFS (HR: 3.99; 95% CI: 1.38-11.54, p = 0.011). No relationship was observed between body composition parameters and grade 3-4 hematological toxicity.</p><p><strong>Conclusion: </strong>The present study supported the significance of sarcopenia and low visceral adipose tissue as potential early indicators of poor PFS in patients treated with CDK 4/6 inhibitors.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"497-507"},"PeriodicalIF":3.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140020981","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
Expression of molecular markers and synergistic anticancer effects of chemotherapy with antimicrobial peptides on glioblastoma cells. 抗菌肽化疗对胶质母细胞瘤细胞的分子标记表达和协同抗癌效应
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-01-27 DOI: 10.1007/s00280-023-04622-8
Alexandr N Chernov, Alexandr V Kim, Sofia S Skliar, Evgeniy V Fedorov, Anna N Tsapieva, Tatiana A Filatenkova, Aleksei L Chutko, Marina V Matsko, Elvira S Galimova, Olga V Shamova

Objective: Glioblastoma multiforme (GBM) is the most aggressive and fatal malignant primary brain tumor. The enhancement of the survival rate for glioma patients remains limited, even with the utilization of a combined treatment approach involving surgery, radiotherapy, and chemotherapy. This study was designed to assess the expression of IDH1, TP53, EGFR, Ki-67, GFAP, H3K27M, MGMT, VEGF, NOS, CD99, and ATRX in glioblastoma tissue from 11 patients. We investigated the anticancer impact and combined effects of cathelicidin (LL-37), protegrin-1 (PG-1), with chemotherapy-temozolomide (TMZ), doxorubicin (DOX), carboplatin (CB), cisplatin (CPL), and etoposide (ETO) in primary GBM cells. In addition, we examined the effect of LL-37, PG-1 on normal human fibroblasts and in the C6/Wistar rat intracerebral glioma model.

Methods: For this study, 11 cases of glioblastoma were evaluated immunohistochemically for IDH1, TP53, EGFR, Ki-67, GFAP, H3K27M, MGMT, VEGF, NOS, CD99, and ATRX. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to study cells viability and to determine cytotoxic effects of LL-37, PG-1 and their combination with chemotherapy in primary GBM cells. Synergism or antagonism was determined using combination index (CI) method. Finally, we established C6 glioblastoma model in Wistar rats to investigate the antitumor activity.

Results: Peptides showed a strong cytotoxic effect on primary GBM cells in the MTT test (IC50 2-16 and 1-32 μM) compared to chemotherapy. The dual-drug combinations of LL-37 + DOX, LL-37 + CB (CI 0.46-0.75) and PG-1 + DOX, PG-1 + CB, PG-1 + TMZ (CI 0.11-0.77), demonstrated a synergism in primary GBM cells. In rat C6 intracerebral GBM model, survival of rats in experimental group (66.75 ± 12.6 days) was prolonged compared with that in control cohort (26.2 ± 2.66 days, p = 0.0008). After LL-37 treatment, experimental group rats showed significantly lower tumor volumes (31.00 ± 8.8 mm3) and weight (49.4 ± 13.3 mg) compared with control group rats (153.8 ± 43.53 mg, p = 0.038; 82.50 ± 7.60 mm3, respectively).

Conclusions: The combination of antimicrobial peptides and chemical drugs enhances the cytotoxicity of chemotherapy and exerts synergistic antitumor effects in primary GBM cells. Moreover, in vivo study provided the first evidence that LL-37 could effectively inhibit brain tumor growth in rat C6 intracerebral GBM model. These results suggested a significant strategy for proposing a promising therapy for the treatment of GBM.

目的:多形性胶质母细胞瘤(GBM多形性胶质母细胞瘤(GBM)是侵袭性最强、最致命的恶性原发性脑肿瘤。即使采用包括手术、放疗和化疗在内的综合治疗方法,胶质瘤患者生存率的提高仍然有限。本研究旨在评估 11 例胶质母细胞瘤患者组织中 IDH1、TP53、表皮生长因子受体、Ki-67、GFAP、H3K27M、MGMT、VEGF、NOS、CD99 和 ATRX 的表达。我们研究了cathelicidin(LL-37)、protegrin-1(PG-1)与化疗--替莫唑胺(TMZ)、多柔比星(DOX)、卡铂(CB)、顺铂(CPL)和依托泊苷(ETO)--对原发性胶质母细胞瘤细胞的抗癌影响和联合作用。此外,我们还研究了 LL-37、PG-1 对正常人成纤维细胞和 C6/Wistar 大鼠脑内胶质瘤模型的影响:本研究对 11 例胶质母细胞瘤进行了免疫组化评估,包括 IDH1、TP53、EGFR、Ki-67、GFAP、H3K27M、MGMT、VEGF、NOS、CD99 和 ATRX。MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)检测法用于研究细胞活力,并确定 LL-37、PG-1 及其与化疗联合使用对原代 GBM 细胞的细胞毒性作用。使用组合指数(CI)法确定协同或拮抗作用。最后,我们在 Wistar 大鼠体内建立了 C6 胶质母细胞瘤模型,以研究其抗肿瘤活性:结果:与化疗相比,肽类药物在 MTT 试验中对原发性 GBM 细胞有很强的细胞毒性作用(IC50 分别为 2-16 和 1-32 μM)。LL-37 + DOX、LL-37 + CB(CI 0.46-0.75)和 PG-1 + DOX、PG-1 + CB、PG-1 + TMZ(CI 0.11-0.77)的双药组合在原发性 GBM 细胞中显示出协同作用。在大鼠 C6 脑内 GBM 模型中,实验组大鼠的存活期(66.75 ± 12.6 天)比对照组大鼠的存活期(26.2 ± 2.66 天,P = 0.0008)更长。经 LL-37 治疗后,实验组大鼠的肿瘤体积(31.00 ± 8.8 mm3)和重量(49.4 ± 13.3 mg)明显低于对照组大鼠(分别为 153.8 ± 43.53 mg,p = 0.038;82.50 ± 7.60 mm3):结论:抗菌肽与化学药物的结合可增强化疗的细胞毒性,并在原发性 GBM 细胞中发挥协同抗肿瘤作用。此外,体内研究首次证明 LL-37 能有效抑制大鼠 C6 脑内 GBM 模型中脑肿瘤的生长。这些结果为提出一种治疗 GBM 的有前途的疗法提供了重要策略。
{"title":"Expression of molecular markers and synergistic anticancer effects of chemotherapy with antimicrobial peptides on glioblastoma cells.","authors":"Alexandr N Chernov, Alexandr V Kim, Sofia S Skliar, Evgeniy V Fedorov, Anna N Tsapieva, Tatiana A Filatenkova, Aleksei L Chutko, Marina V Matsko, Elvira S Galimova, Olga V Shamova","doi":"10.1007/s00280-023-04622-8","DOIUrl":"10.1007/s00280-023-04622-8","url":null,"abstract":"<p><strong>Objective: </strong>Glioblastoma multiforme (GBM) is the most aggressive and fatal malignant primary brain tumor. The enhancement of the survival rate for glioma patients remains limited, even with the utilization of a combined treatment approach involving surgery, radiotherapy, and chemotherapy. This study was designed to assess the expression of IDH1, TP53, EGFR, Ki-67, GFAP, H3K27M, MGMT, VEGF, NOS, CD99, and ATRX in glioblastoma tissue from 11 patients. We investigated the anticancer impact and combined effects of cathelicidin (LL-37), protegrin-1 (PG-1), with chemotherapy-temozolomide (TMZ), doxorubicin (DOX), carboplatin (CB), cisplatin (CPL), and etoposide (ETO) in primary GBM cells. In addition, we examined the effect of LL-37, PG-1 on normal human fibroblasts and in the C6/Wistar rat intracerebral glioma model.</p><p><strong>Methods: </strong>For this study, 11 cases of glioblastoma were evaluated immunohistochemically for IDH1, TP53, EGFR, Ki-67, GFAP, H3K27M, MGMT, VEGF, NOS, CD99, and ATRX. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to study cells viability and to determine cytotoxic effects of LL-37, PG-1 and their combination with chemotherapy in primary GBM cells. Synergism or antagonism was determined using combination index (CI) method. Finally, we established C6 glioblastoma model in Wistar rats to investigate the antitumor activity.</p><p><strong>Results: </strong>Peptides showed a strong cytotoxic effect on primary GBM cells in the MTT test (IC<sub>50</sub> 2-16 and 1-32 μM) compared to chemotherapy. The dual-drug combinations of LL-37 + DOX, LL-37 + CB (CI 0.46-0.75) and PG-1 + DOX, PG-1 + CB, PG-1 + TMZ (CI 0.11-0.77), demonstrated a synergism in primary GBM cells. In rat C6 intracerebral GBM model, survival of rats in experimental group (66.75 ± 12.6 days) was prolonged compared with that in control cohort (26.2 ± 2.66 days, p = 0.0008). After LL-37 treatment, experimental group rats showed significantly lower tumor volumes (31.00 ± 8.8 mm<sup>3</sup>) and weight (49.4 ± 13.3 mg) compared with control group rats (153.8 ± 43.53 mg, p = 0.038; 82.50 ± 7.60 mm<sup>3</sup>, respectively).</p><p><strong>Conclusions: </strong>The combination of antimicrobial peptides and chemical drugs enhances the cytotoxicity of chemotherapy and exerts synergistic antitumor effects in primary GBM cells. Moreover, in vivo study provided the first evidence that LL-37 could effectively inhibit brain tumor growth in rat C6 intracerebral GBM model. These results suggested a significant strategy for proposing a promising therapy for the treatment of GBM.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"455-469"},"PeriodicalIF":3.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139569881","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
Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation. 钌-二氢青蒿素复合物:通过 G1 细胞周期阻滞、凋亡诱导和适应性免疫调节预防结肠癌的前景广阔的新化合物。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-01-09 DOI: 10.1007/s00280-023-04623-7
Chong-Zhi Wang, Chunping Wan, Cang-Hai Li, Guo-Gang Liang, Yun Luo, Chun-Feng Zhang, Qi-Hui Zhang, Qinge Ma, Angela H Wang, Mallory Lager, Ting-Liang Jiang, Lifei Hou, Chun-Su Yuan

Background: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies.

Methods: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties.

Results: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1β, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation.

Conclusions: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

背景:青蒿素(ART)及其衍生物是重要的抗疟疾药物,由于其广泛的生物医学效应,如抗癌和抗炎活性,已受到越来越多的关注。最近,由于在临床前和临床研究中观察到其抗癌潜力,钌衍生复合物引起了广泛关注:为了探索一种治疗结直肠癌(CRC)的创新方法,我们合成了一种新型金属基青蒿素衍生物分子--钌-二氢青蒿素复合物(D-Ru),并研究了它的抗癌、抗炎和适应性免疫调节特性:与母体化合物 ART 相比,D-Ru 对人 CRC 细胞株 HCT-116 和 HT-29 具有更强的抗增殖作用。D-Ru 对癌细胞的抑制作用包括通过下调细胞周期蛋白 A 和诱导细胞凋亡实现 G1 细胞周期的停滞。ART 和 D-Ru 下调了促炎细胞因子 IL-1β、IL-6 和 IL-8 的表达。虽然 ART 和 D-Ru 没有抑制 Treg 细胞的分化,但它们显著抑制了 Th1 和 Th17 细胞的分化:我们的研究结果表明,D-Ru 是 ART 的一种新型钌复合物,它能显著增强母体化合物的抗癌作用,而抗炎潜力却没有受到影响。D-Ru 的分子作用机制包括通过抑制细胞周期来抑制癌细胞生长、诱导细胞凋亡以及通过调节适应性免疫来抗炎。
{"title":"Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation.","authors":"Chong-Zhi Wang, Chunping Wan, Cang-Hai Li, Guo-Gang Liang, Yun Luo, Chun-Feng Zhang, Qi-Hui Zhang, Qinge Ma, Angela H Wang, Mallory Lager, Ting-Liang Jiang, Lifei Hou, Chun-Su Yuan","doi":"10.1007/s00280-023-04623-7","DOIUrl":"10.1007/s00280-023-04623-7","url":null,"abstract":"<p><strong>Background: </strong>Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies.</p><p><strong>Methods: </strong>To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties.</p><p><strong>Results: </strong>Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1β, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation.</p><p><strong>Conclusions: </strong>Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"411-425"},"PeriodicalIF":3.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139402019","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
Evaluation of ABT-751, a novel anti-mitotic agent able to overcome multi-drug resistance, in melanoma cells. 在黑色素瘤细胞中评估能够克服多重耐药性的新型抗有丝分裂剂 ABT-751。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-01-16 DOI: 10.1007/s00280-023-04624-6
Thamir M Mahgoub, Emmet J Jordan, Amira F Mahdi, Veronika Oettl, Stefanie Huefner, Norma O'Donovan, John Crown, Denis M Collins

Purpose: Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemotherapies for the treatment of metastatic melanoma. ABT-751 is an orally bioavailable microtubule-binding agent capable of overcoming MDR and proposed as an alternative to taxane-based therapies.

Methods: This study compares ABT-751 to taxanes in vitro, utilizing seven melanoma cell line models, publicly available gene expression and drug sensitivity databases, a lung cancer cell line model of MDR drug efflux transporter overexpression (DLKP-A), and drug efflux transporter ATPase assays.

Results: Melanoma cell lines exhibit a low but variable protein and RNA expression of drug efflux transporters P-gp, BCRP, and MDR3. Expression of P-gp and MDR3 correlates with sensitivity to taxanes, but not to ABT-751. The anti-proliferative IC50 profile of ABT-751 was higher than the taxanes docetaxel and paclitaxel in the melanoma cell line panel, but fell within clinically achievable parameters. ABT-751 IC50 was not impacted by P-gp-overexpression in DKLP-A cells, which display strong resistance to the P-gp substrate taxanes compared to DLKP parental controls. The addition of ABT-751 to paclitaxel treatment significantly decreased cell proliferation, suggesting some reversal of MDR. ATPase activity assays suggest that ABT-751 is a potential BCRP substrate, with the ability to inhibit P-gp ATPase activity.

Conclusion: Our study confirms that ABT-751 is active against melanoma cell lines and models of MDR at physiologically relevant concentrations, it inhibits P-gp ATPase activity, and it may be a BCRP and/or MDR3 substrate. ABT-751 warrants further investigation alone or in tandem with other drug efflux transporter inhibitors for hard-to-treat MDR melanoma.

目的:与药物外排转运体相关的多药耐药性(MDR)是使用类固醇类化学疗法治疗转移性黑色素瘤的潜在限制因素。ABT-751是一种口服生物型微管结合剂,能够克服MDR,被建议作为基于类固醇的疗法的替代品:本研究利用七个黑色素瘤细胞系模型、可公开获得的基因表达和药物敏感性数据库、MDR 药物外排转运体过表达的肺癌细胞系模型(DLKP-A)以及药物外排转运体 ATP 酶测定,在体外对 ABT-751 和紫杉类药物进行了比较:结果:黑色素瘤细胞系的药物外排转运体 P-gp、BCRP 和 MDR3 的蛋白和 RNA 表达量较低,但可变。P-gp 和 MDR3 的表达与对紫杉类药物的敏感性有关,但与对 ABT-751 的敏感性无关。在黑色素瘤细胞系研究小组中,ABT-751的抗增殖半数致死浓度(IC50)高于多西他赛和紫杉醇类药物,但在临床可达到的参数范围内。ABT-751 IC50不受DKLP-A细胞中P-gp过表达的影响,与DLKP亲代对照组相比,DKLP-A细胞对P-gp底物紫杉类药物有很强的抗药性。在紫杉醇治疗中加入 ABT-751 会显著降低细胞增殖,这表明 MDR 在一定程度上发生了逆转。ATP酶活性测定表明,ABT-751是一种潜在的BCRP底物,具有抑制P-gp ATP酶活性的能力:我们的研究证实,ABT-751 在生理相关浓度下对黑色素瘤细胞系和 MDR 模型具有活性,它能抑制 P-gp ATPase 活性,而且可能是 BCRP 和/或 MDR3 底物。对于难以治疗的MDR黑色素瘤,ABT-751值得单独或与其他药物外排转运抑制剂一起进一步研究。
{"title":"Evaluation of ABT-751, a novel anti-mitotic agent able to overcome multi-drug resistance, in melanoma cells.","authors":"Thamir M Mahgoub, Emmet J Jordan, Amira F Mahdi, Veronika Oettl, Stefanie Huefner, Norma O'Donovan, John Crown, Denis M Collins","doi":"10.1007/s00280-023-04624-6","DOIUrl":"10.1007/s00280-023-04624-6","url":null,"abstract":"<p><strong>Purpose: </strong>Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemotherapies for the treatment of metastatic melanoma. ABT-751 is an orally bioavailable microtubule-binding agent capable of overcoming MDR and proposed as an alternative to taxane-based therapies.</p><p><strong>Methods: </strong>This study compares ABT-751 to taxanes in vitro, utilizing seven melanoma cell line models, publicly available gene expression and drug sensitivity databases, a lung cancer cell line model of MDR drug efflux transporter overexpression (DLKP-A), and drug efflux transporter ATPase assays.</p><p><strong>Results: </strong>Melanoma cell lines exhibit a low but variable protein and RNA expression of drug efflux transporters P-gp, BCRP, and MDR3. Expression of P-gp and MDR3 correlates with sensitivity to taxanes, but not to ABT-751. The anti-proliferative IC<sub>50</sub> profile of ABT-751 was higher than the taxanes docetaxel and paclitaxel in the melanoma cell line panel, but fell within clinically achievable parameters. ABT-751 IC<sub>50</sub> was not impacted by P-gp-overexpression in DKLP-A cells, which display strong resistance to the P-gp substrate taxanes compared to DLKP parental controls. The addition of ABT-751 to paclitaxel treatment significantly decreased cell proliferation, suggesting some reversal of MDR. ATPase activity assays suggest that ABT-751 is a potential BCRP substrate, with the ability to inhibit P-gp ATPase activity.</p><p><strong>Conclusion: </strong>Our study confirms that ABT-751 is active against melanoma cell lines and models of MDR at physiologically relevant concentrations, it inhibits P-gp ATPase activity, and it may be a BCRP and/or MDR3 substrate. ABT-751 warrants further investigation alone or in tandem with other drug efflux transporter inhibitors for hard-to-treat MDR melanoma.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"427-437"},"PeriodicalIF":3.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472325","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
Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients TACR1 基因多态性是预测神经激肽-1 受体拮抗剂止吐方案反应的潜在药物遗传学因素:乳腺癌患者候选基因关联研究
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-04-27 DOI: 10.1007/s00280-024-04661-9
Marziyeh Ghorbani, Soha Namazi, Mehdi Dehghani, Farideh Razi, Bahman Khalvati, Ali Dehshahri

Purpose

The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens.

Methods

A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA.

Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000).

Results

Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue.

Conclusion

Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers.

目的目前的候选基因关联研究旨在调查 TACR1 基因的标记 SNPs 作为止吐指南推荐的基于 NK-1 受体拮抗剂的三联止吐方案反应的药物遗传学预测因子。方法采用实时 PCR-HRMA 技术对接受蒽环类和环磷酰胺(含/不含多西他赛)治疗的乳腺癌患者的 18 个 TACR1 标记 SNPs 进行基因分型。.1.使用PLINK(分别为v.1.9和v.1.07)对每个标记SNP和单倍型等位基因与未能达到规定的止吐疗效终点之间的关系进行了基于逻辑回归的测试,并对之前已知的化疗引起的恶心和呕吐(CINV)预后因素进行了调整。结果rs881、rs17010730、rs727156和rs3755462四个变异以及包含上述变异的单倍型与至少一个疗效终点的失败显著相关。通过内嵌研究进行的变异注释显示,非种子序列变异 rs881 位于 miRNA(hsa-miR-613)结合位点。结论 TACR1基因多态性在调控TACR1表达中发挥着重要作用,是预测NK-1受体拮抗剂三联止吐方案反应的潜在药物遗传学因素。如果获得临床批准,调整 NK-1 受体拮抗剂的剂量就能更好地控制风险等位基因携带者的 CINV。
{"title":"Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients","authors":"Marziyeh Ghorbani, Soha Namazi, Mehdi Dehghani, Farideh Razi, Bahman Khalvati, Ali Dehshahri","doi":"10.1007/s00280-024-04661-9","DOIUrl":"https://doi.org/10.1007/s00280-024-04661-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>The current candidate gene association study aims to investigate tag SNPs from the <i>TACR1</i> gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A set of eighteen tag SNPs of <i>TACR1</i> were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA.</p><p>Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported <i>p</i>-values were corrected using the permutation test (n = 100,000).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Playing an essential role in regulating <i>TACR1</i> expression, gene polymorphisms of <i>TACR1</i> serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"75 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140811437","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
Preventive effect of free radical scavenger edaravone lotion on cyclophosphamide chemotherapy-induced alopecia 自由基清除剂依达拉奉洗剂对环磷酰胺化疗所致脱发的预防作用
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-04-20 DOI: 10.1007/s00280-024-04669-1
Takumi Tsuji, Katsuaki Yoneda, Yu Igawa, Erika Minamino, Nodoka Otani, Yuya Yoshida, Takeyuki Kohno

Purpose

We investigated the inhibitory effect of edaravone (EDR) lotion on chemotherapy-induced alopecia (CIA) to improve the quality of life for patients with cancer.

Methods

Wistar rats were intraperitoneally injected with cyclophosphamide (CPA, 75 mg/kg) to induce CIA and divided into six groups: (1) Control; (2) EDR 0%; (3) EDR 0.3%; (4) EDR 3%. The TUNEL-positive area was examined histologically, and mRNA expression levels of the apoptosis-related factors, such as B-cell/CLL lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax), were determined.

Results

In the three CPA-treated groups, a decrease in the coverage score (percentage of hairs covered) was observed from days 16 to 18. In addition, coverage scores on day 21, the last day of observation, showed a tendency for the suppression of hair loss to increase, though hair loss was observed in all groups. The coverage scores of the EDR 0.3% and 3% groups after day 17 were significantly higher than those of the EDR 0% group. The TUNEL-positive area of skin tissue on day 16 was extensive in the EDR 0% group and decreased in the EDR 0.3% and 3% groups. The mRNA expression ratio of Bcl-2/Bax on day 21 was maintained at the same level as that of the control group only in the EDR 3% group.

Conclusion

This study confirmed the use of EDR lotion to inhibit hair loss, indicating that the clinical application of EDR lotion may improve the quality of life for patients with cancer and their willingness to undergo treatment.

目的 我们研究了依达拉奉(EDR)洗剂对化疗诱导性脱发(CIA)的抑制作用,以改善癌症患者的生活质量。方法 给Wistar大鼠腹腔注射环磷酰胺(CPA,75 mg/kg)诱导CIA,分为6组:(1)对照组;(2)EDR 0%组;(3)EDR 0.3%组;(4)EDR 3%组。对 TUNEL 阳性区域进行组织学检查,并测定 B 细胞/CLL 淋巴瘤 2(Bcl-2)和 Bcl-2 相关 X 蛋白(Bax)等凋亡相关因子的 mRNA 表达水平。此外,第 21 天(观察的最后一天)的覆盖率评分显示,脱发抑制率呈上升趋势,尽管所有组别都观察到脱发现象。第 17 天后,EDR 0.3% 和 3% 组的覆盖度评分明显高于 EDR 0% 组。第 16 天,EDR 0% 组皮肤组织的 TUNEL 阳性面积较大,而 EDR 0.3% 和 3% 组则有所减少。结论本研究证实了使用 EDR 洗剂可抑制脱发,表明临床应用 EDR 洗剂可提高癌症患者的生活质量和接受治疗的意愿。
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引用次数: 0
Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors 晚期实体瘤患者服用卡匹伐替和 CYP3A4 底物咪达唑仑的药代动力学研究
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-04-20 DOI: 10.1007/s00280-024-04667-3
Claire Miller, Roberto Sommavilla, Cindy L. O’Bryant, Minal Barve, Afshin Dowlati, Jason J. Luke, Mahmuda Khatun, Thomas Morris, Marie Cullberg

Purpose

Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug–drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors.

Methods

Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted.

Results

Capivasertib–midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUCinf and Cmax was 1.13 (0.97–1.32) and 1.15 (0.99–1.33) for day 8 versus day 1, and 1.75 (1.50–2.05) and 1.25 (1.08–1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment.

Conclusion

The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population.

ClinicalTrials.gov: NCT04958226.

目的 卡匹伐他替(capivasertib)是一种对所有三种AKT丝氨酸/苏氨酸激酶(AKT)同工酶都有效的选择性抑制剂,目前正在晚期乳腺癌和前列腺癌的3期试验中进行评估。本研究评估了卡非伐他汀与细胞色素P450 3A底物咪达唑仑在既往接受过治疗的晚期实体瘤成人患者中的药物相互作用风险。方法患者从第1周期(29天)的第2天开始,在此后每个28天周期的第1天按间歇计划(开4天/关3天)口服卡非伐他汀400毫克,每天两次(BID)。仅在第1周期,患者在第1天(单独用药)、第8天和第12天(分别为服用卡匹伐他汀的第3天和第4天)口服咪达唑仑(1毫克)。第 8 天和第 12 天的咪达唑仑药代动力学与第 1 天进行了对比分析。认为可能获益的患者可继续接受卡匹伐他汀治疗或不接受标准护理治疗。结果卡匹伐他汀与咪达唑仑联合用药增加了咪达唑仑的暴露量(n = 21):第8天与第1天相比,AUCinf和Cmax的几何平均比值(90%置信区间)分别为1.13(0.97-1.32)和1.15(0.99-1.33);第12天与第1天相比,分别为1.75(1.50-2.05)和1.25(1.08-1.46)。在使用或不使用咪达唑仑的情况下,卡匹伐他汀的安全性是可控的。结论:咪达唑仑的暴露量增加了1.75倍,这表明卡匹伐他汀是一种弱CYP3A抑制剂,间歇给药400毫克,每日一次。Capivasertib的耐受性良好;探索性疗效分析表明,在这种重度预处理人群中,Capivasertib具有临床活性:NCT04958226。
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引用次数: 0
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Cancer Chemotherapy and Pharmacology
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