Cancer Chemotherapy and Pharmacology最新文献

{"title":"AKR1C4 regulates the sensitivity of colorectal cancer cells to chemotherapy through ferroptosis modulation.","authors":"Li Wang, Cuiling Lv, Xiaoxia Liu","doi":"10.1007/s00280-024-04685-1","DOIUrl":"10.1007/s00280-024-04685-1","url":null,"abstract":"<p><strong>Purpose: </strong>Colorectal cancer (CRC) remains a major global health concern, necessitating innovative therapeutic strategies to enhance treatment efficacy. In this study, we investigated the role of AKR1C4 in CRC and its impact on chemotherapy response.</p><p><strong>Methods: </strong>AKR1C4 stable knockout CRC cell lines were generated using CRISPR/Cas9 technology. The impact of AKR1C4 depletion on chemotherapy sensitivity was assessed using Sulforhodamine B assay. Long-term, low-dose drug induction with increasing concentrations of 5FU, irinotecan, and oxaliplatin were employed to establish acquired chemoresistant CRC cell lines. Ferroptosis induction and inhibition were examined through total iron content and lipid peroxidation measurements.</p><p><strong>Results: </strong>We found that AKR1C4 knockout enhances CRC cell sensitivity to chemotherapy, specifically by inducing ferroptosis. The enzymatic activity of AKR1C4 is crucial for regulating chemotherapy sensitivity in CRC cells, as evidenced by the inability of a Y55A mutant to reverse the sensitizing effect. Additionally, AKR1C4 inhibitors enhance chemotherapy sensitivity by inducing ferroptosis. Notably, AKR1C4 depletion resensitizes the acquired chemoresistant CRC cells to chemotherapy, suggesting its potential as a therapeutic target for overcoming acquired chemoresistance. Clinical analysis reveals that high AKR1C4 expression is associated with poor prognosis in CRC patients undergoing chemotherapy, highlighting its significance as a prognostic marker and a potential target for therapeutic intervention.</p><p><strong>Conclusion: </strong>This study illuminates the multifaceted role of AKR1C4 in CRC, demonstrating its significance in regulating chemotherapy sensitivity, overcoming acquired resistance, and impacting clinical outcomes. The insights provided may pave the way for novel therapeutic strategies in CRC management.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"373-385"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417949","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}

{"title":"Correction to: Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.","authors":"Romain Sechaud, Helen Gu, Gholamreza Rahmanzadeh, Amanda Taylor, Ovidiu Chiparus, Gopal Krishna Sharma, Astrid Breitschaft, Hans D Menssen","doi":"10.1007/s00280-024-04657-5","DOIUrl":"10.1007/s00280-024-04657-5","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"487"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027487","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}

{"title":"Evaluation of the effect of modafinil on the pharmacokinetics of encorafenib and binimetinib in patients with BRAF V600-mutant advanced solid tumors.","authors":"Joseph Piscitelli, Micaela B Reddy, Lance Wollenberg, Laurence Del Frari, Jason Gong, Kyle Matschke, Jason H Williams","doi":"10.1007/s00280-024-04676-2","DOIUrl":"10.1007/s00280-024-04676-2","url":null,"abstract":"<p><strong>Background: </strong>A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer at a 400 mg QD dose, on the multiple oral dose pharmacokinetics (PK) of encorafenib and its metabolite, LHY746 and binimetinib and its metabolite, AR00426032.</p><p><strong>Methods: </strong>This study was conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 h on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects.</p><p><strong>Results: </strong>Among 11 PK evaluable patients, encorafenib C_max and AUC_last were decreased in presence of steady-state modafinil by 20.2% and 23.8%, respectively. LHY746 exposures were not substantially changed in the presence of steady-state modafinil.</p><p><strong>Conclusion: </strong>The results from this clinical study indicate modafinil 400 mg QD had a weak effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov NCT03864042, registered 6 March 2019.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"337-347"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327263","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}

{"title":"Alterations in pharmacogenetic genes and their implications for imatinib resistance in Chronic Myeloid Leukemia patients from an admixed population.","authors":"Karla Beatriz Cardias Cereja-Pantoja, Tereza Cristina de Brito Azevedo, Lui Wallacy Morikawa Souza Vinagre, Francisco Cezar Aquino de Moraes, Giovanna Gilioli da Costa Nunes, Natasha Monte, Angélica Leite de Alcântara, Amanda Cohen-Paes, Marianne Rodrigues Fernandes, Sidney Emanuel Batista Dos Santos, Paulo Pimentel de Assumpção, Ândrea Kely Ribeiro Dos Santos, Rommel Mario Rodríguez Burbano, Raquel Cruz Guerrero, Ángel Carracedo, Ney Pereira Carneiro Dos Santos","doi":"10.1007/s00280-024-04689-x","DOIUrl":"10.1007/s00280-024-04689-x","url":null,"abstract":"<p><p>Imatinib is the tyrosine kinase inhibitor used as the gold standard for the treatment of Chronic Myeloid Leukemia. However, about 30% of patients do not respond well to this therapy. Variants in drug administration, distribution, metabolism and excretion (ADME) genes play an important role in drug resistance especially in admixed populations. We investigated 129 patients diagnosed with Chronic Myeloid Leukemia treated with imatinib as first choice therapy. The participants of the study are highly admixed, populations that exhibit genetic diversity and complexity due to the contributions of multiple ancestral groups. Thus, the aim of this work was to investigate the association of 30 SNVs in genes related to response to treatment with Imatinibe in CML. Our results indicated that for the rs2290573 of the ULK3 gene, patients with the recessive AA genotype are three times more likely to develop resistance over time (secondary resistance) (p = 0.019, OR = 3.19, IC 95%= 1.21-8.36). Finally, we performed interaction analysis between the investigated variants and found several associations between SNVs and secondary resistance. We concluded that the variant rs2290573 of the ULK3 gene may be relevant for predicting treatment response of CML with imatinib, as well as possible treatment resistance. The use of predictive biomarkers is an important tool for therapeutic choice of patients, improving their quality of life and treatment efficacy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"387-395"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417952","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}

{"title":"ZNF384 transcriptionally activated MGST1 to confer TMZ resistance of glioma cells by negatively regulating ferroptosis.","authors":"Tengfeng Yan, Ping Hu, Shigang Lv, Minhua Ye, Miaojing Wu, Hua Fang, Bing Xiao","doi":"10.1007/s00280-024-04681-5","DOIUrl":"10.1007/s00280-024-04681-5","url":null,"abstract":"<p><strong>Background: </strong>Drug resistance is one of the major reasons of the poor prognosis and recurs frequently in glioma. Ferroptosis is considered to be a new therapeutic strategy for glioma.</p><p><strong>Methods: </strong>Microsomal glutathione S-transferase 1 (MGST1) expression in glioma samples was ensured through GAPIA database, qRT-PCR, western blotting assay and immunohistochemistry. The interaction between zinc finger protein 384 (ZNF384) and MGST1 promoter was analyzed through UCSC and JASPAR databases and further verified by ChIP and luciferase reporter assay. Cell viability and IC50 value of temozolomide (TMZ) was measured by CCK-8 assay. The production of MDA, GSH and ROS and the level of Fe²⁺ were determined using the corresponding kit.</p><p><strong>Results: </strong>MGST1 expression was increased in clinical glioma tissues and glioma cells. MGST1 expression was increased but ferroptosis was suppressed in TMZ-resistant cells when contrasted to parent cells. MGST1 silencing downregulated IC50 value of TMZ and cell viability but facilitated ferroptosis in TMZ-resistant cells and parent glioma cells. Moreover, our data indicated that ZNF384 interacted with MGST1 promoter and facilitated MGST1 expression. ZNF384 was also increased expression in TMZ-resistant cells, and showed a positive correlation with MGST1 expression in clinical level. ZNF384 decreasing enhanced the sensitivity of resistant cells to TMZ, while the effect of ZNF384 could be reversed by overexpression of MGST1.</p><p><strong>Conclusion: </strong>MGST1 transcription is regulated by transcription factor ZNF384 in TMZ-resistant cells. ZNF384 confers the resistance of glioma cells to TMZ through inhibition of ferroptosis by positively regulating MGST1 expression. The current study may provide some new understand to the mechanism of TMZ resistance in glioma.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"323-336"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186491","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}

{"title":"Oral docetaxel plus encequidar - a phase 1 clinical trial.","authors":"David Wang, Noelyn Hung, Tak Hung, Karen Eden, Wing-Kai Chan, Rudolf Kwan, Albert Qin, Cynthia Chang, Stephen Duffull, Paul Glue, Christopher Jackson","doi":"10.1007/s00280-024-04674-4","DOIUrl":"10.1007/s00280-024-04674-4","url":null,"abstract":"<p><strong>Purpose: </strong>To determine the bioavailability, safety, and tolerability of a single dose of oral docetaxel plus encequidar (oDox + E) and compare its pharmacokinetic exposure with current standard of care IV docetaxel.</p><p><strong>Introduction: </strong>Docetaxel is a taxane widely used as an anti-neoplastic agent. Due to low oral bioavailability secondary to gut P-glycoprotein (P-gp) efflux, its current use is limited to intravenous administration. Oral docetaxel may provide a less resource intensive, more convenient, and tolerable alternative. Encequidar is a first in class, minimally absorbed, oral gut-specific P-gp inhibitor. We tested whether oDox + E can achieve comparable pharmacokinetic exposure to IV docetaxel.</p><p><strong>Methods: </strong>A multicentre, phase I open-label, pharmacokinetic trial was undertaken to determine the bioavailability, safety, and tolerability of a single dose of oDox + E (at 75 mg/m2 + 15 mg, 150 mg/m2 + 15 mg, and 300 mg/m2 + 15 mg) in metastatic prostate cancer (mPC) patients compared to standard of care IV docetaxel as prescribed by their oncologists. The 15 mg of Encequidar at each dose level was given one hour prior to oral docetaxel.</p><p><strong>Results: </strong>11 patients were enrolled; 9 patients completed the study. Oral docetaxel exposure increased with dose, achieving the highest at 300 mg/m2 oDox + E (with AUC_{0 - infinity} of 1343.3 ± 443.0 ng.h/mL compared to the IV docetaxel AUC_{0 - infinity} of 2000 ± 325 ng.h/mL) and became non-linear at 300 mg/m². The mean absolute bioavailability of oDox + E across all 3 dose levels was 16.14% (range: 8.19-25.09%). No patient deaths, dose limiting toxicity, treatment-related serious adverse event or grade 4 toxicity were observed. Maximal tolerated dose was not reached.</p><p><strong>Conclusion: </strong>oDox + E has a safe and tolerable adverse event profile in patients with metastatic prostate cancer. The increase in oral bioavailability of oDox + E suggests a multi-dose oDox + E regimen could theoretically achieve exposures comparable with standard of care IV docetaxel. Further development to examine the optimal multiple dose regimen of oDox + E is warranted.</p><p><strong>Trial registration number: </strong>U1111-1173-5473.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"475-481"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174903","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}

{"title":"Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.","authors":"Anna M Mc Laughlin, Dagmar Hess, Robin Michelet, Ilaria Colombo, Simon Haefliger, Sara Bastian, Manuela Rabaglio, Michael Schwitter, Stefanie Fischer, Katrin Eckhardt, Stefanie Hayoz, Christoph Kopp, Marian Klose, Cristiana Sessa, Anastasios Stathis, Stefan Halbherr, Wilhelm Huisinga, Markus Joerger, Charlotte Kloft","doi":"10.1007/s00280-024-04679-z","DOIUrl":"10.1007/s00280-024-04679-z","url":null,"abstract":"<p><strong>Study objectives: </strong>TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling.</p><p><strong>Methods: </strong>The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicin_entrapped, doxorubicin_free, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored.</p><p><strong>Results: </strong>Medians  <math><mo>±</mo></math> standard deviations of dose-normalised doxorubicin_{entrapped+free} C_max and AUC_0-∞ were 0.342 <math><mo>±</mo></math> 0.134 mg/L and 40.1 <math><mo>±</mo></math> 18.9 mg·h/L, respectively. The median half-life (95 h) was 23.5 h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicin_entrapped), a two-compartment model with linear elimination (doxorubicin_free), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate.</p><p><strong>Conclusion: </strong>The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov-NCT03387917-January 2, 2018.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"349-360"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327264","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}

{"title":"Postoperative chemotherapy relative dose intensity and overall survival in patients with colon cancer.","authors":"Justin C Brown, Jeffrey A Meyerhardt, Shengping Yang, Bette J Caan","doi":"10.1007/s00280-024-04665-5","DOIUrl":"10.1007/s00280-024-04665-5","url":null,"abstract":"<p><strong>Purpose: </strong>Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit.</p><p><strong>Methods: </strong>This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR).</p><p><strong>Results: </strong>Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)].</p><p><strong>Conclusion: </strong>If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"461-465"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193446","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}

{"title":"Correction to: Inhibition of proteinase-activated receptor 2 (PAR2) decreased the malignant progression of lung cancer cells and increased the sensitivity to chemotherapy.","authors":"Hongjie Huo, Yu Feng, Qiong Tang","doi":"10.1007/s00280-024-04646-8","DOIUrl":"10.1007/s00280-024-04646-8","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"489"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292893","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}

{"title":"Non-linear IV pharmacokinetics of the ATR inhibitor berzosertib (M6620) in mice.","authors":"Joshua J Deppas, Brian F Kiesel, Jianxia Guo, Robert A Parise, D Andy Clump, David Z D'Argenio, Christopher J Bakkenist, Jan H Beumer","doi":"10.1007/s00280-024-04675-3","DOIUrl":"10.1007/s00280-024-04675-3","url":null,"abstract":"<p><strong>Background: </strong>The Ataxia Telangiectasia and Rad3-related (ATR) protein complex is an apical initiator of DNA damage response pathways. Several ATR inhibitors (ATRi) are in clinical development including berzosertib (formerly M6620, VX-970). Although clinical studies have examined plasma pharmacokinetics (PK) in humans, little is known regarding dose/exposure relationships and tissue distribution. To understand these concepts, we extensively characterized the PK of berzosertib in mouse plasma and tissues.</p><p><strong>Methods: </strong>A highly sensitive LC-MS/MS method was utilized to quantitate berzosertib in plasma and tissues. Dose proportionality was assessed in female BALB/c mice following single IV doses (2, 6, 20 or 60 mg/kg). A more extensive PK study was conducted in tumor-bearing mice following a single IV dose of 20 mg/kg to evaluate distribution to tissues. PK parameters were calculated by non-compartmental analysis (NCA). A compartmental model was developed to describe the PK behavior of berzosertib. Plasma protein binding was determined in vitro.</p><p><strong>Results: </strong>Increased doses of berzosertib were associated with less than proportional increases in early plasma concentrations and greater than proportional increase in tissue exposure, attributable to saturation of plasma protein binding. Berzosertib extensively distributed into bone marrow, tumor, thymus, and lymph nodes, however; brain and spinal cord exposure was less than plasma.</p><p><strong>Conclusion: </strong>The nonlinear PK of berzosertib displayed here can be attributed to saturation of plasma protein binding and occurred at concentrations close to those observed in clinical trials. Our results will help to understand preclinical pharmacodynamic and toxicity data and to inform optimal dosing and deployment of berzosertib.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"271-283"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920930","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}