Cancer Chemotherapy and Pharmacology最新文献

{"title":"Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.","authors":"Geraldine O'Sullivan Coyne, Shivaani Kummar, Larry V Rubinstein, Deborah Wilsker, Nancy Moore, Murielle Hogu, Richard Piekarz, Joe Covey, Jan H Beumer, Katherine V Ferry-Galow, Liza C Villaruz, Melinda G Hollingshead, Julianne L Holleran, Joshua J Deppas, Yves Pommier, Brian Ko, Barry C Johnson, Ralph E Parchhment, Percy Ivy, James H Doroshow, Alice P Chen","doi":"10.1007/s00280-025-04778-5","DOIUrl":"10.1007/s00280-025-04778-5","url":null,"abstract":"<p><strong>Purpose: </strong>Indenoisoquinolines are a class of topoisomerase I (TOP1) inhibitors designed to overcome clinical limitations of camptothecins. Three indenoisoquinolines (LMP400, LMP776, and LMP744) demonstrated activity in murine models and a comparative canine lymphoma study. Clinical data for LMP400 were previously reported (NCT01051635). The maximum tolerated dose (MTD), safety, and clinical data from phase 1 studies of LMP776 (NCT01051635) and LMP744 (NCT03030417) are reported herein.</p><p><strong>Methods: </strong>Patients ≥ 18 years of age with advanced, refractory solid tumors or lymphomas received either LMP776 (n = 34) or LMP744 (n = 35) intravenously following a Simon accelerated titration design. Both LMP776 and LMP744 were administered daily for 5 days (QDx5) in 28-day cycles. Adverse events and clinical responses were evaluated according to CTCAE and RECIST v1.1 criteria, respectively. Pharmacokinetic and pharmacodynamic changes were evaluated.</p><p><strong>Results: </strong>The MTD of LMP776 was 12 mg/m²/day and that of LMP744 was 190 mg/m²/day. Dose-limiting toxicities (DLTs) for LMP776 included hypercalcemia, anemia, and hyponatremia; DLTs for LMP744 included hypokalemia, anemia, and weight loss. There was 1 confirmed partial response (cPR) among 35 patients receiving LMP744 (overall response rate 3%) and no objective responses in patients receiving LMP776. Tumor biopsies from the patient with cPR demonstrated high baseline expression of SLFN11 and a unique pattern of pharmacodynamic responses, including increased RAD51, phosphorylated KAP1 (pKAP1), γH2AX, and cleaved caspase-3 (cCasp3).</p><p><strong>Conclusion: </strong>MTDs and safety profiles are reported for LMP776 and LMP744. Target engagement by an indenoisoquinoline was measured for the first time in human samples.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"58"},"PeriodicalIF":2.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172534","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":"Pharmacokinetics, mass balance, and metabolism of [¹⁴C]FCN-437c, a selective and potent CDK4/6 inhibitor in humans.","authors":"Lei Gao, Sheng Ma, Shu Yan, Hua Zhang, Ling Tian, Lize Li, Lei Diao, Liyan Miao, Xiaoran Yang, Xingxing Diao","doi":"10.1007/s00280-025-04779-4","DOIUrl":"https://doi.org/10.1007/s00280-025-04779-4","url":null,"abstract":"<p><p>This study investigated the pharmacokinetics, mass balance, and metabolism of [¹⁴C]FCN-437c, a selective and potent CDK4/6 inhibitor, in humans. Six healthy male Chinese subjects were administered a single oral dose of 200 mg [¹⁴C]FCN-437c (120 µCi), and plasma, urine, and feces samples were collected up to 456 h post-dose. The geometric mean C_max of radioactivity in plasma and blood were 706 and 557 ng eq./mL, respectively, with a median T_max of 5.0 h and a geometric mean t_1/2 of 56.5 h in plasma. The primary route of elimination was fecal excretion, accounting for a mean of 77.16% of the dose, whereas urinary excretion constituted a mean of 19.19% of the administered radioactivity. UHPLC-HRMS analysis identified 12 metabolites in human plasma, urine, and feces, with 8 of them being phase I metabolites, and the major metabolic pathways were mono-oxidation and O-dealkylation. Additionally, 4 phase II metabolites were identified, including two glucuronides, one glutathione conjugate, and one cysteine conjugate. The study provides insights into the metabolic stability and clearance mechanisms of FCN-437c in human, which are essential for its further clinical development and dosing regimens.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"57"},"PeriodicalIF":2.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141269","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":"Pharmacokinetic profile of novel reduced-dose Danziten^™ (nilotinib tablets) versus Tasigna^® (nilotinib capsules): in vivo bioequivalence and population pharmacokinetic analysis.","authors":"Michael Mauro, Jerald Radich, Paras Jain, David Sequeira, Francesco Bellanti, Dan Douer","doi":"10.1007/s00280-025-04777-6","DOIUrl":"https://doi.org/10.1007/s00280-025-04777-6","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate single dose pharmacokinetics (PK) of novel reduced-dose film coated Danziten^™ (nilotinib tablets) using a population PK approach, establish bioequivalence vs. Tasigna^® (nilotinib capsules) and investigate food effects on PK of both formulations.</p><p><strong>Methods: </strong>A population PK model evaluating nilotinib capsules (300 or 400 mg) or tablets (142 or 190 mg) was developed using data from 14 single dose studies and > 30,000 plasma samples from healthy men and women. Steady-state nilotinib concentration-time profiles following twice daily dosing with various treatment and food conditions were simulated using a randomly sampled dataset of 50 subjects.</p><p><strong>Results: </strong>PK was characterized by a 2-compartment model with linear elimination and zero-order absorption with lag time. Bioequivalence was met for all steady state exposure metrics for both doses under fasted conditions. A milligram strength for nilotinib tablets ~ 50% lower than that for capsules resulted in bioequivalent nilotinib exposures. Administration with a low-fat meal under modified fasting conditions increased the bioavailability (BA) of 142 mg and 190 mg nilotinib tablets by 26.0% and 29.3%, respectively, vs. fasting; values for 300 mg and 400 mg capsules were 56.8% and 60.7%. Administration with a high-fat meal under modified fasting conditions increased the BA of 142 and 190 mg nilotinib tablets by 48.6% and 52.2%, respectively; values for 300 and 400 mg capsules were 180.6% and 183.3%.</p><p><strong>Conclusion: </strong>Nilotinib tablets 142 and 190 mg provide bioequivalent exposures to 300 mg and 400 mg capsules under fasted conditions and substantially smaller effects of food on exposure.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"56"},"PeriodicalIF":2.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062426","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":"Potential role of endothelial dysfunction in hypertension and proteinuria in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab: a pilot prospective observational study.","authors":"Satoru Nihei, Kazuki Saito, Tatsuki Ikeda, Takayoshi Oikawa, Koichi Asahi, Junichi Asaka, Kenzo Kudo","doi":"10.1007/s00280-025-04776-7","DOIUrl":"https://doi.org/10.1007/s00280-025-04776-7","url":null,"abstract":"<p><strong>Purpose: </strong>Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Its inhibition of VEGF signaling may lead to proteinuria due to endothelial dysfunction but the association between endothelial function and clinical outcomes has not been established. This study aimed to investigate vascular endothelial function in patients with HCC receiving atezolizumab plus bevacizumab, and to assess the correlation between reactive hyperemia index (RHI) and adverse renal outcomes.</p><p><strong>Methods: </strong>This pilot prospective observational study included 20 patients with HCC who received atezolizumab plus bevacizumab. We used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of RHI. RHI, blood pressure, and proteinuria were recorded at baseline and at 3 and 6 months after initiation of atezolizumab plus bevacizumab treatment. Statistical analyses were performed to investigate the relationship of RHI to blood pressure and proteinuria.</p><p><strong>Results: </strong>Following initiation of atezolizumab plus bevacizumab treatment, systolic blood pressure and urine protein-creatinine ratio increased significantly, and RHI decreased. Patients with borderline or low baseline RHI had a higher incidence of grade ≥ 2 proteinuria than those with normal baseline RHI but not hypertension. A significant inverse correlation was found between RHI and urine protein-creatinine ratio.</p><p><strong>Conclusion: </strong>Bevacizumab administration may cause endothelial dysfunction in patients with HCC. The vascular endothelial function status before and during atezolizumab plus bevacizumab treatment is associated with the risk of bevacizumab-induced proteinuria.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"55"},"PeriodicalIF":2.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062428","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":"Pharmacokinetics, metabolism, and excretion of [¹⁴C]-valemetostat in healthy male participants, and in vitro plasma protein binding.","authors":"Masaya Tachibana, Nicholas Siebers, Thuy Vu Craveiro, Miho Kazui, Tomoko Ikeda, Takako Shimizu, Shinichi Inaba, Malaz A Abutarif","doi":"10.1007/s00280-025-04771-y","DOIUrl":"https://doi.org/10.1007/s00280-025-04771-y","url":null,"abstract":"<p><strong>Introduction: </strong>Valemetostat tosylate (valemetostat) is an oral, selective, dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1. This article reports findings on the mass balance and pharmacokinetics of valemetostat in a phase I study; valemetostat metabolite identification in plasma, urine, and fecal samples; and plasma-protein-binding of valemetostat in vitro.</p><p><strong>Methods: </strong>Eight healthy participants received a single 200-mg oral dose of [¹⁴C]-valemetostat under fasting conditions. Blood, urine, and feces samples were collected to determine total radioactivity and/or unchanged valemetostat, and for metabolite identification. The binding of valemetostat 600-10,000 ng/mL to plasma, 4% human serum albumin (HSA), and 0.1% alpha-1-acid glycoprotein (AAG) was assessed in vitro.</p><p><strong>Results: </strong>Mean cumulative recovery of administered radioactivity was 95.3% by 360 h post-dose, with a mean recovery of 15.6% in urine and 79.8% in feces. Valemetostat accounted for the most radioactivity in the excreta, at 10% and 64.9% of the administered dose in the urine and feces, respectively. CALZ-1809a was the most abundant metabolite, present in all biological samples, and accounted for 5.6% of total radioactivity in the feces. Valemetostat was minimally associated with red blood cells, with a blood-to-plasma total radioactivity ratio of 0.54. In vitro, valemetostat was highly plasma-bound (> 94%) at clinically relevant concentrations, with a higher affinity to AAG than to HSA.</p><p><strong>Conclusion: </strong>Valemetostat was rapidly absorbed into the systemic circulation, mainly excreted via the biliary/fecal route, primarily metabolized by CYP3A enzymes to CALZ-1809a, and highly bound to plasma proteins, with a greater affinity to AAG than HSA in vitro.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"54"},"PeriodicalIF":2.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11985606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954908","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":"Neurofilament light chain as a marker for neuronal damage: integrating in vitro studies and clinical findings in patients with oxaliplatin-induced neuropathy.","authors":"Nina Lykkegaard Gehr, Christina Mortensen, Tore B Stage, Malene Roland Vils Pedersen, Søren Rafael Rafaelsen, Jonna Skov Madsen, Dorte Aalund Olsen, Signe Timm, Lars Henrik Jensen, Torben Frøstrup Hansen, Nanna Brix Finnerup, Lise Ventzel","doi":"10.1007/s00280-025-04773-w","DOIUrl":"https://doi.org/10.1007/s00280-025-04773-w","url":null,"abstract":"<p><strong>Purpose: </strong>Oxaliplatin-induced peripheral neuropathy (OIPN) is a chronic, debilitating late effect following oxaliplatin treatment. Neurofilament light chain (NfL) is a structural protein found in nerve axons that was investigated upon oxaliplatin exposure in vitro and in vivo correlated to symptoms of OIPN in colorectal cancer patients receiving oxaliplatin.</p><p><strong>Methods: </strong>Human sensory neurons, derived from induced pluripotent stem cells, were exposed to clinically relevant concentrations of oxaliplatin in vitro, with NfL concentrations measured in the cell medium. The prospective clinical study included patients with colorectal cancer undergoing chemotherapy therapy with or without oxaliplatin. Possible OIPN was defined as bilateral presence of numbness and/or presence of pricking sensations in the feet documented in an interview at the time of blood sampling prior to, 3, and 6 months after initiating treatment.</p><p><strong>Results: </strong>Oxaliplatin exposure led to a dose-dependent NfL increase in vitro. In the clinical cohort of 30 patients (18 in the oxaliplatin group), NfL levels rose at 3 and 6 months compared to controls. NfL level changes correlated to OIPN symptoms at the 6-month timepoint (rho 0.81, p < 0.001). However, the interindividual variation was substantial, and most patients showed only a minor increase in NfL.</p><p><strong>Conclusion: </strong>Both in vitro and clinical data indicate that oxaliplatin exposure results in elevated NfL levels. Further prospective studies are needed to evaluate NfL as an early biomarker for OIPN, specifically focusing on the timing of blood sampling during chemotherapy treatment to enable the timely reduction of oxaliplatin.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"53"},"PeriodicalIF":2.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11985616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954614","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":"Evolution of computational techniques against various KRAS mutants in search for therapeutic drugs: a review article.","authors":"Ayesha Mehmood, Mohammed Ageeli Hakami, Hanan A Ogaly, Vetriselvan Subramaniyan, Asaad Khalid, Abdul Wadood","doi":"10.1007/s00280-025-04767-8","DOIUrl":"10.1007/s00280-025-04767-8","url":null,"abstract":"<p><p>KRAS was (Kirsten rat sarcoma viral oncogene homolog) revealed as an important target in current therapeutic cancer research because alteration of RAS (rat sarcoma viral oncogene homolog) protein has a critical role in malignant modification, tumor angiogenesis, and metastasis. For cancer treatment, designing competitive inhibitors for this attractive target was difficult. Nevertheless, computational investigations of the protein's dynamic behavior displayed the existence of temporary pockets that could be used to design allosteric inhibitors. The last decade witnessed intensive efforts to discover KRAS inhibitors. In 2021, the first KRAS G12C covalent inhibitor, AMG 510, received FDA (Food and drug administration) approval as an anticancer medication that paved the path for future treatment strategies against this target. Computer-aided drug designing discovery has long been used in drug development research targeting different KRAS mutants. In this review, the major breakthroughs in computational methods adapted to discover novel compounds for different mutations have been discussed. Undoubtedly, virtual screening and molecular dynamic (MD) simulation and molecular docking are the most considered approach, producing hits that can be employed in subsequent refinements. After comprehensive analysis, Afatinib and Quercetin were computationally identified as hits in different publications. Several authors conducted covalent docking studies with acryl amide warheads groups containing inhibitors. Future studies are needed to demonstrate their true potential. In-depth studies focusing on various allosteric pockets demonstrate that the switch I/II pocket is a suitable site for drug designing. In addition, machine learning and deep learning based approaches provide new insights for developing anti-KRAS drugs. We believe that this review provides extensive information to researchers globally and encourages further development in this particular area of research.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"52"},"PeriodicalIF":2.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802617","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":"Napabucasin targets resistant triple negative breast cancer through suppressing STAT3 and mitochondrial function.","authors":"Limei Yuan, Yaqing Zhu, Gege Guan, Mei Liu","doi":"10.1007/s00280-025-04770-z","DOIUrl":"10.1007/s00280-025-04770-z","url":null,"abstract":"<p><p>Chemoresistance in triple negative breast cancer (TNBC) poses a significant challenge in effective treatment, necessitating the exploration of novel therapeutic strategies. This study evaluates the efficacy of napabucasin, a potent STAT3 inhibitor, in two paclitaxel-resistant TNBC cell models (MD-MBA-231-r and BT-549-r). We observed that napabucasin significantly reduced cell viability and colony formation in a dose-dependent manner. Combination index analysis revealed synergistic interactions between napabucasin and paclitaxel, suggesting enhanced cytotoxic effects when used in combination. Mechanistically, napabucasin inhibited STAT3 signaling and impaired mitochondrial function, as evidenced by decreased phosphorylated STAT3 levels, reduced mitochondrial complex I activity, lower oxygen consumption rate and diminished ATP levels. Further analysis indicated that paclitaxel-resistant cells exhibit higher mitochondrial biogenesis and function compared to their sensitive counterparts, with elevated expression of mitochondrial genes and biogenesis regulators, and increased levels of mitochondrial respiration. In vivo, napabucasin significantly inhibited tumor growth in paclitaxel-resistant TNBC xenograft models and reduced the expression of proliferation marker Ki67 and phosphorylation of STAT3. These findings demonstrate that napabucasin effectively targets paclitaxel-resistant TNBC cells by impairing mitochondrial function and inhibiting key signaling pathways, providing a strong rationale for its further clinical investigation as a therapeutic agent to overcome chemoresistance in TBNC.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"51"},"PeriodicalIF":2.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762978","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":"The evaluation of the impact of NUDT15 variants on thiopurine metabolism in Japanese children with acute lymphoblastic leukemia.","authors":"Yoichi Tanaka, Rintaro Ono, Miho Ashiarai, Ayako Sakurai, Atsushi Watanabe, Taichiro Tsuchimochi, Yosuke Hosoya, Ruri Hanajiri, Takeshi Inukai, Daisuke Hasegawa","doi":"10.1007/s00280-025-04774-9","DOIUrl":"10.1007/s00280-025-04774-9","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL).</p><p><strong>Methods: </strong>DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing.</p><p><strong>Results: </strong>Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p < 0.01). The ranges of DNA-TG/dose and DNA-TG/Ery-TGNs ratio were not different within NUDT15 phenotypes. In NUDT15 NM, patients with high Ery-TGNs/dose showed high DNA-TG/dose. Absolute lymphocyte count was significantly correlated with DNA-TG, Ery-TGNs, and Ery-MMPN levels (p < 0.001). White blood cell counts were significantly correlated with Ery-TGNs levels (p < 0.02), and the levels of aspartate and alanine aminotransferases were significantly correlated with Ery-MMPN levels (p < 0.001).</p><p><strong>Conclusion: </strong>NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"50"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762979","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":"Influence of interleukin-6 on the pharmacokinetics and pharmacodynamics of osimertinib in patients with non-small cell lung cancer.","authors":"Hayato Yokota, Kazuhiro Sato, Sho Sakamoto, Yuji Okuda, Masahide Takeda, Yumiko Akamine, Katsutoshi Nakayama, Masatomo Miura","doi":"10.1007/s00280-025-04772-x","DOIUrl":"10.1007/s00280-025-04772-x","url":null,"abstract":"<p><strong>Purpose: </strong>The inflammatory cytokine interleukin (IL)-6 reduces the activity of drug metabolic enzymes and promotes tumor progression. We investigated the effect of IL-6 on the pharmacokinetics of osimertinib and the association between an IL-6 polymorphism and clinical outcomes in 30 patients with non-small cell lung cancer (NSCLC).</p><p><strong>Methods: </strong>Osimertinib and IL-6 plasma concentrations were measured on day 15 after therapy initiation. The genotype of IL-6 1800796G > C was identified using polymerase chain reaction-restriction fragment length polymorphism. Risk factors affecting overall survival (OS) were assessed by Cox proportional hazard regression analysis.</p><p><strong>Results: </strong>The IL-6 concentration was significantly correlated with the osimertinib trough plasma concentration (r = 0.423, P = 0.020) and area under the plasma concentration-time curve (r = 0.420, P = 0.021). The IL-6 concentration was significantly higher in patients with the IL-6 rs1800796G allele versus C/C genotype (P = 0.024). OS was significantly shorter in patients with the IL-6 rs1800796G allele versus C/C genotype (median: 15.1 vs. 48.9 months, P = 0.005). Univariate and multivariate analyses indicated that the IL-6 rs1800796G allele is an independent risk factor for OS (crude hazard ratio = 7.07; P = 0.014; adjusted hazard ratio = 6.38; P = 0.021).</p><p><strong>Conclusion: </strong>A higher IL-6 concentration was associated with reduced metabolic activity of osimertinib, leading to increased osimertinib exposure. As the IL-6 concentration was higher in NSCLC patients with the IL-6 rs1800796G allele, it might be an independent prognostic factor for patients treated with osimertinib.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"49"},"PeriodicalIF":2.7,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742543","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}