Cancer Chemotherapy and Pharmacology最新文献

{"title":"Tenuigenin inhibits osteosarcoma growth via CIP2A/PP2A/NF-κB axis.","authors":"Shuo Yang, Shasha Liu, Zixun Dai","doi":"10.1007/s00280-024-04733-w","DOIUrl":"https://doi.org/10.1007/s00280-024-04733-w","url":null,"abstract":"<p><strong>Background: </strong>Polygala tenuifolia and its active components have been revealed to possess anti-tumor activities. However, the role of Tenuigenin (TEN), a bioactive ingredient from Polygala tenuifolia, in tumors such as osteosarcoma (OS) remains unclear. The present research intended to explore the efficacy and underlying mechanism of TEN on OS.</p><p><strong>Methods: </strong>OS cells were administrated with different concentrations of TEN. Cell viability, proliferation, invasion, and migration were assessed with CCK-8 assay, colony formation assay, transwell assay, and wound healing assay, respectively. Protein and mRNA levels were determined with western blot and qRT-PCR, while protein phosphatase 2A (PP2A) activity was tested with PP2A phosphatase assay kit. The interaction between PP2A and cancerous inhibitor of protein phosphatase 2A (CIP2A) or nuclear factor kappaB (NF-κB) signaling was detected using co-immunoprecipitation. p-p65 expression in the nucleus was determined with immunofluorescence. The efficacy of TEN in vivo was also explored in a xenograft tumor model. Immunohistochemistry was performed to detect CIP2A and Ki67 in mice.</p><p><strong>Results: </strong>TEN treatment or CIP2A depletion repressed cell viability, proliferation, invasion, and migration in OS cells. Additionally, TEN reduced CIP2A, increased PP2A activity, and inactivated NF-κB signaling. PP2A directly interacted with CIP2A or NF-κB signaling, and PP2A inhibition reversed CIP2A knockdown-induced repression of NF-κB signaling. CIP2A overexpression overturned the efficacy of TEN, which was reversed by NF-κB inhibition. TEN decreased CIP2A, elevated PP2A activity, inactivated NF-κB signaling, and inhibited tumor growth in vivo, which was antagonized by CIP2A overexpression.</p><p><strong>Conclusion: </strong>TEN suppressed OS growth via CIP2A/PP2A/NF-κB axis, indicating that it would be a novel drug for treating OS.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"15"},"PeriodicalIF":2.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variations in serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment.","authors":"Miki Takenaka Sato, Takuya Araki, Hideaki Yashima, Yuya Ishikawa, Jun Morita, Yoshiko Maeda, Masayuki Ohbayashi, Noriko Kohyama, Yoshio Ogawa, Takashi Fukagai, Koujirou Yamamoto, Mari Kogo","doi":"10.1007/s00280-024-04741-w","DOIUrl":"10.1007/s00280-024-04741-w","url":null,"abstract":"<p><strong>Purpose: </strong>The blood concentrations of some tyrosine kinase inhibitors are known to decrease with long-term administration. We evaluated the variability in the serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment.</p><p><strong>Methods: </strong>This study prospectively recruited patients who received sunitinib for metastatic renal cell carcinoma at the Showa University Hospital between March 2020 and January 2022. Bivariate correlations between the serum concentration/dose (C/D) ratios of sunitinib and its metabolites (i.e., N-desethyl sunitinib and sunitinib N-oxide) and treatment duration were evaluated using Pearson's correlation coefficient.</p><p><strong>Results: </strong>Seven patients were enrolled, and 79 blood samples were collected. Among six patients who received sunitinib for > 1 year, three showed a decreasing trend in the C/D ratio of sunitinib (Pt1: r = -0.608, p = 0.047; Pt2: r = -0.555, p = 0.077; Pt6: r = -0.590, p = 0.073). In these patients, the median annual decrease in the C/D ratio of sunitinib was 55.8% (26.5-63.2%). Additionally, two of the three patients also showed a decrease in the C/D ratio of N-desethyl sunitinib. The ratio of N-desethyl sunitinib/sunitinib concentration at baseline and the end of follow-up was similar between the C/D-decreased and C/D-non-decreased groups.</p><p><strong>Conclusion: </strong>This study showed that the C/D ratio of sunitinib decreased by half over time in half of the patients who received long-term sunitinib treatment despite continuing the same dose. Therefore, serum concentrations of sunitinib and its metabolites should be monitored periodically in patients receiving long-term treatment to prevent decrease in serum sunitinib concentrations.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"14"},"PeriodicalIF":2.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of cisplatin in the systemic versus hyperthermic intrathoracic or intraperitoneal chemotherapy.","authors":"Tao Zhang, Wei Mu, Cheng-Gong Liao, Yan Hou, Jie Song, Wen Hu, Yun Wang, Dongxu Chen, Yu Chen, Linna Liu, Lili Liu","doi":"10.1007/s00280-024-04727-8","DOIUrl":"10.1007/s00280-024-04727-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To compare the pharmacokinetics and adverse effects of cisplatin administered via intravenous infusion for systemic chemotherapy (SC) versus injection into the perfusate during hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Total 60 patients who received SC, HITHOC, or HIPEC in the Department of Oncology, Tangdu Hospital, were enrolled into this study. After administering same dose of cisplatin (40 mg) via either intravenous infusion (SC group) or injection into the perfusate during the HITHOC or HIPEC procedure, concentration of cisplatin in the plasma as well as in the hyperthermic perfusate at various time points was quantified by HPLC analysis. The area under the plasma or perfusate concentration-time curve over the last 24h dosing interval (AUC&lt;sub&gt;0-24h&lt;/sub&gt;), mean residence time over the 24 h (MRT&lt;sub&gt;0-24h&lt;/sub&gt;), terminal elimination half-life (t&lt;sub&gt;1/2z&lt;/sub&gt;), time to peak concentration (T&lt;sub&gt;max&lt;/sub&gt;), apparent clearance (Clz/F), and peak concentration (C&lt;sub&gt;max&lt;/sub&gt;) in the perfusate and plasma were compared.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In the perfusate, the AUC&lt;sub&gt;0-24h&lt;/sub&gt; (64.32 ± 27.12 µg/mL·h) and C&lt;sub&gt;max&lt;/sub&gt; (21.62 ± 5.88 µg/mL) were significantly higher in the HITHOC group compared to that in the HIPEC group (31.68 ± 13.29 µg/mL·h and 16.96 ± 5.54 µg/mL, respectively, p ≤ 0.01). In contrast, MRT&lt;sub&gt;0-∞&lt;/sub&gt;, t&lt;sub&gt;1/2z&lt;/sub&gt;, and Clz/F were significantly lower in the HITHOC group compared to that in the HIPEC group (p &lt; 0.01). In the plasma, average AUC&lt;sub&gt;0-24h&lt;/sub&gt; and C&lt;sub&gt;max&lt;/sub&gt; of the HITHOC group were 2.57 ± 0.55 µg/mL·h and 0.26 ± 0.08 µg/mL, respectively, which were significantly lower than that of systemic chemotherapy (SC) group (3.26 ± 0.56 µg/mL·h and 0.69 ± 0.14 µg/mL, respectively, p &lt; 0.01), but no difference compared to that of HIPEC group (3.02 ± 0.52 µg/mL·h and 0.40 ± 0.15 µg/mL, respectively, p &gt; 0.05). In contrast, MRT&lt;sub&gt;0-24h&lt;/sub&gt; and T&lt;sub&gt;max&lt;/sub&gt; in the plasma of HITHOC group were significantly longer compared to that of SC group (p &lt; 0.05), but no significant difference compared to that of HIPEC group (p &gt; 0.05). Absolute bioavailability of cisplatin in the thoracic (HITHOC group) and abdominal (HIPEC group) cavities was 20 and 10 times higher than that in the blood administered intravenously (SC group), respectively. There was no significant difference in the incidence of adverse events among the three groups (p &lt; 0.05).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The current study demonstrated that, in the perfusate, AUC&lt;sub&gt;0-24h&lt;/sub&gt; and C&lt;sub&gt;max&lt;/sub&gt; of cisplatin was significantly higher in the group of HITHOC compared to that of HIPEC, and that, in the plasma, AUC&lt;sub&gt;0-24h&lt;/sub&gt; and C&lt;sub&gt;max&lt;/sub&gt; of cisplatin was lower in the group of HITHOC compared to that of HIPEC or SC group. This study provided pharmacokinetic evidence to further support the concep","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"13"},"PeriodicalIF":2.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892383","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":"HER-2 SMASH.","authors":"Celal Alandağ, Ayşegül Öztürk, Fatih Yulak, Zeynep Deniz Şahin İnan, Mustafa Karaca, Burak Batuhan Lacın, Ahmet Altun","doi":"10.1007/s00280-024-04726-9","DOIUrl":"https://doi.org/10.1007/s00280-024-04726-9","url":null,"abstract":"<p><strong>Purpose: </strong>Human epidermal growth factor-2 (HER-2) targeted drugs are used in only HER-2 overexpressed cancers. However, only a small portion of these cancer types are HER-2 overexpressed. In this study, we aimed to upregulate HER-2 receptors in MCF-7 breast cancer and HT-29 colon cancer cell cultures, which these cells are not HER-2 upregulated in natural status.</p><p><strong>Methods: </strong>We used a 10-day non-cytotoxic lapatinib dose to upregulate HER-2 receptors. HER-2 levels of these cell lines were tested with ELISA and immunofluorescence tests before and after 10 days of lapatinib administration. After upregulation of HER-2, we administered trastuzumab, and T-DM1 to these cell lines to observe whether there is an increase in anticancer activity. We used a cell viability test to show the cytotoxicity of trastuzumab and T-DM1. Also, we used ELISA and immunofluorescence for HER-2 pathway proteins to understand the mechanism of increased anti-cancer activity.</p><p><strong>Results: </strong>We showed that administration of lapatinib for 10 days leads to overexpression of HER-2 receptors on both MCF-7 and HT-29 cells. A significant increase in the cytotoxicity of trastuzumab or T-DM1 was observed after 10 days of lapatinib administration.</p><p><strong>Conclusion: </strong>We named this method the smash method, which is the volleyball term. In volleyball, the ball is raised while low and quickly hits the ground again, just like we do with the HER-2 receptor. The smash method can switch HER-2 negative or HER-2 low tumors into HER-2 overexpressed, iatrogenically. Thus, we can use her2-targeted therapies in all cancer patients instead of a small portion.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"10"},"PeriodicalIF":2.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876230","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 urinary vanin-1 for the early prediction of cisplatin-induced acute kidney injury during neoadjuvant chemotherapy for esophageal cancer.","authors":"Tomonobu Uchino, Yuna Iwano, Yasunori Miyazaki, Michiaki Nakajo, Misa Osawa, Erina Nagai, Yusuke Taki, Shinsuke Sato, Masaya Watanabe, Masakazu Takagi, Yoshiyuki Kagawa","doi":"10.1007/s00280-024-04737-6","DOIUrl":"https://doi.org/10.1007/s00280-024-04737-6","url":null,"abstract":"<p><strong>Purpose: </strong>Cisplatin (CDDP) induces acute kidney injury (AKI) as a side effect during neoadjuvant chemotherapy (NAC). Urinary vanin-1 excretion may increase during CDDP treatment. We investigated whether urinary vanin-1 is an early biomarker for CDDP-induced AKI.</p><p><strong>Methods: </strong>Thirty patients were administered 80 mg/m² CDDP on day 1 as NAC for esophageal cancer. Blood and urine samples were collected on days 1, 2, 3, 4, and 6 after CDDP administration. Serum creatinine (sCr) and urinary vanin-1 levels were measured. Creatinine clearance (cCr) and estimated glomerular filtration rate (eGFR) were calculated from sCr. Based on the change in sCr after CDDP administration, the AKI and non-AKI groups were defined using the Kidney Disease Improving Global Outcomes classification. Changes in sCr, cCr, eGFR, and urinary vanin-1 levels were compared between the two groups.</p><p><strong>Results: </strong>A gradual increase in sCr and a decrease in eGFR were observed over time post-CDDP administration, with differences between the two groups becoming significant by day 4. However, urinary vanin-1 levels increased on day 3 after CDDP administration, and the difference between the two groups was significant on day 3. Receiver operating characteristic curves of urinary vanin-1 on day 3 revealed that a cut-off value of 3.17 ng urinary vanin-1/mg urinary creatinine yielded an area under the curve, sensitivity, and specificity of 0.83 (P < 0.05), 75.0%, and 22.7%, respectively. The non-AKI incidence below the cut-off value of urinary vanin-1 of 3.17 ng/mg uCr was 89.5%.</p><p><strong>Conclusion: </strong>Urinary vanin-1 is a superior minimally invasive biomarker for the early prediction of CDDP-induced AKI.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"11"},"PeriodicalIF":2.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876208","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 CYP2C8*3 and ABCG2 C421A genetic polymorphisms on trough concentration and molecular response of imatinib in Egyptian patients with chronic myeloid leukemia.","authors":"Safwat A Mangoura, Mahmoud H Abdel-Raheem, Hanan A Eltyb, Mohammed S Molla, Abeer M R Hussein","doi":"10.1007/s00280-024-04723-y","DOIUrl":"10.1007/s00280-024-04723-y","url":null,"abstract":"<p><strong>Purpose: </strong>The treatment landscape for chronic myeloid leukemia (CML) has been revolutionized by the introduction of imatinib, a tyrosine kinase inhibitor, which has transformed the disease from a fatal condition into a manageable chronic illness for a substantial number of patients. Despite this, some individuals do not respond adequately to the treatment, and others may experience disease progression even with continued therapy. This study examined how CYP2C8*3 (G416A; rs11572080) and ABCG2 C421A (rs2231142) single nucleotide polymorphisms (SNPs) affect the plasma trough concentration and therapeutic response of imatinib in Egyptian CML patients.</p><p><strong>Methods: </strong>The study included fifty patients with chronic-phase CML, who were categorized into two groups: responders (n = 26) and non-responders (n = 24), according to their BCR-ABL1 transcription levels after 12 months of imatinib treatment. Genotyping of the CYP2C8*3 and ABCG2 C421A polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while plasma trough concentrations were determined through high-performance liquid chromatography with ultraviolet-diode array detection (HPLC-UV/DAD).</p><p><strong>Results: </strong>Patients with the CA genotype of ABCG2 C421A showed significantly higher mean plasma trough concentrations of imatinib (CA: 1731 ± 424.7 ng/mL; CC: 1294 ± 381.3 ng/mL; p = 0.0132) and demonstrated a better molecular response compared to those with the CC genotype (p = 0.0395).</p><p><strong>Conclusion: </strong>The ABCG2 C421A polymorphism significantly influenced imatinib plasma trough concentrations and molecular responses in Egyptian chronic-phase CML patients. Genotyping of this polymorphism in these patients could assist in optimizing imatinib therapy, predicting more favorable treatment outcomes, and enabling the development of more personalized treatment plans.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"12"},"PeriodicalIF":2.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876232","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":"Plasma clearance of 5-fluorouracil is more influenced by variations in glomerular filtration rate than by uracil concentration.","authors":"Alice Matheux, Laurine Collas, Maelle Grisard, Léa Goulaieff, François Ghiringhelli, Leïla Bengrine-Lefevre, Julie Vincent, Francoise Goirand, Bernard Royer, Antonin Schmitt","doi":"10.1007/s00280-024-04732-x","DOIUrl":"https://doi.org/10.1007/s00280-024-04732-x","url":null,"abstract":"<p><strong>Objectives: </strong>The use of plasma uracil measurements to detect dihydropyrimidine dehydrogenase (DPD) deficiency is one of the methods for preventing toxicities associated with fluoropyrimidines, including 5-Fluorouracil (5-FU). Unfortunately, this measurement is subject to variations, that may lead to unnecessary dosage reductions and therefore to a reduced efficacy of treatment. Recently, new factors such as hepatic and renal impairment have been proposed as also influencing uracil concentration. The aim of our study was therefore to study the influence of renal or hepatic function on 5-FU clearance.</p><p><strong>Patients and methods: </strong>This was a retrospective study, using patients treated with 5-FU between September 1, 2018 to December 1, 2022 in a French Clinical Cancer Center. Patients were included after treatment with 5FU and therapeutic monitoring of 5FU concentrations after each course of chemotherapy. For each patient, DPD phenotyping by uracil concentration measurement was determined before the first course of 5FU. Blood samples were then taken the day after the start of the 5-FU infusion, between 8 and 10 am, for the first three cycles of 5-FU. With the exception of uracil concentration, which was determined only once, the various data were recorded for each course of 5FU chemotherapy performed. Patients with incomplete information (missing one of the above parameters) were excluded from the database.</p><p><strong>Results: </strong>We included 227 patients, corresponding to 227 uracil concentrations and 575 5-FU concentrations. In an original development, our results show for the first time that 5-FU clearance was proportionally correlated with eGFR (calculated according to CKD-EPI formula). Although we failed to demonstrate this hypothesis significantly, we observed that 5-FU clearance may be more dependent on eGFR than on uracil concentration for low uracil concentrations values.</p><p><strong>Conclusion: </strong>Our study reinforces the still poorly accepted idea of the value of focusing on eGFR in 5-FU dose adjustment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"9"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863452","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":"Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRAS^G12C inhibitor.","authors":"Lisa Rahbaek, Cornelius Cilliers, Christopher J Wegerski, Natalie Nguyen, Jennifer Otten, Lauren Hargis, Matthew A Marx, James G Christensen, Jonathan Q Tran","doi":"10.1007/s00280-024-04728-7","DOIUrl":"https://doi.org/10.1007/s00280-024-04728-7","url":null,"abstract":"<p><strong>Objective: </strong>This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600 mg dose (1 µCi [¹⁴C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600 mg twice daily.</p><p><strong>Methods: </strong>Plasma, urine, and feces were collected post [¹⁴C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine. The steady-state plasma metabolite profile was examined in patients and in vitro studies were performed to understand adagrasib's potential to inhibit CYP enzymes and identify CYPs involved in its metabolism.</p><p><strong>Results: </strong>The total mean recovery of the administered radioactivity was 79.2%, with 74.7% and 4.49% of total radioactivity recovered from feces and urine, respectively. Only 1.8% of the dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance. Adagrasib, M55a, M11, and M68 were major plasma components accounting for 38.3%, 13.6%, 13.4%, and 11.0% of the total plasma radioactivity exposure, respectively. Metabolite M55a was not detected in plasma at steady state where only M68 (24%) and M11 (17.1%) were abundant. In vitro data showed that CYP3A4 (72%) and CYP2C8 (28%) are main contributors to metabolism and adagrasib is a time-dependent inhibitor of CYP3A4.</p><p><strong>Conclusion: </strong>Elimination of adagrasib is mainly by fecal excretion. Adagrasibs altered metabolite profile at steady state is likely due to CYP3A4 autoinhibition. The abundant steady-state plasma metabolites, M68 and M11, are not human specific and do not contribute significantly to the pharmacological activity of adagrasib.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"7"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852945","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":"Predictive factors for first dose reduction and interruption of lenvatinib after beginning of the standard dose in Japanese patients with thyroid cancer.","authors":"Kazuma Fujita, Mitsuji Nagahama, Akifumi Suzuki, Chie Masaki, Kiminori Sugino, Koichi Ito, Masatomo Miura","doi":"10.1007/s00280-024-04729-6","DOIUrl":"10.1007/s00280-024-04729-6","url":null,"abstract":"<p><strong>Purpose: </strong>The associations between first dose reduction or interruption by side effects and lenvatinib plasma trough concentration (C₀) after administration of a starting dose of 24 mg in 70 Japanese patients with thyroid cancer were evaluated.</p><p><strong>Methods: </strong>Plasma samples were collected each week for 1 month and at the first incidence of side effects leading to dose reduction or interruption after beginning administration of 24 mg lenvatinib.</p><p><strong>Results: </strong>The area under the receiver operating characteristic curve was 0.789 at a lenvatinib C₀ threshold of 128.25 ng/mL for predicting the first dose reduction or interruption. The median time to the first dose reduction or interruption was 14.0 days in patients with a C₀ of ≥ 128.25 ng/mL and 21.0 days in those with a C₀ of < 128.25 ng/mL (P = 0.001). At one, two, three and four weeks respectively, the first dose reduction or interruption was associated with body weight (P = 0.034); sex (P = 0.021); sex, age, and lenvatinib C₀ of ≥ 128.25 ng/mL (P = 0.025, 0.024, and 0.048, respectively); and age and lenvatinib C₀ of ≥ 128.25 ng/mL (each P = 0.004).</p><p><strong>Conclusions: </strong>On day 8 after administration of 24 mg lenvatinib, lenvatinib dose may be adjusted based on the target C₀ of 128.25 ng/mL to maintain a high dose intensity during this early phase; however, because persistence of a higher C₀ of 128.25 ng/mL causes early dose interruption or reduction, prospective dose reduction based on the next lower target C₀ for the maintenance phase may be necessary.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"8"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863461","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":"Intrathecal pemetrexed for leptomeningeal metastases in a patient with ALK-rearranged lung adenocarcinoma: a case report.","authors":"Emelie Gezelius, Maria Planck, Bassam Hazem, Seema Nagpal, Heather Wakelee","doi":"10.1007/s00280-024-04735-8","DOIUrl":"10.1007/s00280-024-04735-8","url":null,"abstract":"<p><p>Progressive leptomeningeal metastases (LM) are associated with intractable neurological symptoms and a poor prognosis, and effective treatment options are limited. Intrathecal (IT) pemetrexed has been shown to confer clinical benefit in lung adenocarcinoma, yet our understanding of the efficacy and safety of the treatment is limited. We report a patient with a long-standing history of leptomeningeal disease due to ALK-positive adenocarcinoma of the lung, previously controlled by increased doses of lorlatinib (125 mg/day). Rapid LM progression prompted the start of IT pemetrexed, after which the patient experienced immediate clinical improvement. The case provides additional support that IT pemetrexed can offer symptomatic relief and may be considered as a treatment option in advanced LM. Furthermore, the case illustrates that an increased dose of lorlatinib may efficiently control LM in patients with ALK-rearranged NSCLC, following progression on standard lorlatinib dosage.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"6"},"PeriodicalIF":2.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833917","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}