Cancer Chemotherapy and Pharmacology最新文献

{"title":"Targeting on the PI3K/mTOR: a potential treatment strategy for clear cell ovarian carcinoma.","authors":"Kewei Zheng, Guanqin Jin, Rui Cao, Yi Gao, Jing Xu, Ranran Chai, Yu Kang","doi":"10.1007/s00280-024-04748-3","DOIUrl":"https://doi.org/10.1007/s00280-024-04748-3","url":null,"abstract":"<p><strong>Purpose: </strong>Ovarian clear cell carcinoma is a highly malignant gynecological tumor characterized by a high rate of chemotherapy resistance and poor prognosis. The PI3K/AKT/mTOR pathway is well-known to be closely related to the progression of various malignancies, and recent studies have indicated that this pathway may play a critical role in the progression and worsening of OCCC.</p><p><strong>Methods: </strong>In this study, we investigated the combined effects of WX390, a dual inhibitor of PI3K/mTOR, and cisplatin on OCCC through both in vitro and in vivo experiments to further elucidate their therapeutic effects.</p><p><strong>Results: </strong>WX390 significantly inhibited the proliferation of human OCCC cell lines ES2 and OVISE, while promoting apoptosis. Furthermore, the combination of WX390 with CDDP exhibited a synergistic effect, markedly increasing the sensitivity of OCCC cells to chemotherapeutic agents and significantly suppressing tumor growth in PDX models. Western blot and RNA-seq analyses revealed that WX390 robustly inhibited the PI3K/AKT/mTOR pathway, interrupt autophagy, altered cell cycle dynamics, and induced apoptosis.</p><p><strong>Conclusion: </strong>This study comprehensively assessed the efficacy of WX390 across multiple models of OCCC, laying a solid foundation for the development of new therapeutic strategies for this challenging malignancy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"21"},"PeriodicalIF":2.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945192","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":"Endoglin as a predictive biomarker for pemetrexed sensitivity in non-small-cell lung cancer: a cellular study.","authors":"Ching-Yuan Cheng, Wen-Chen Chuang, Ching-Pin Lin, Che-Hsing Li, Hui-Yi Chang, Wen-Jun Wu, Ming-Fang Wu, Jiunn-Liang Ko","doi":"10.1007/s00280-024-04734-9","DOIUrl":"https://doi.org/10.1007/s00280-024-04734-9","url":null,"abstract":"<p><strong>Objective: </strong>Based on our previous research, which demonstrated that elevated plasma endoglin (ENG) levels in lung cancer patients were associated with a better prognosis, increased sensitivity to pemetrexed, and enhanced tumor suppression, this study aims to validate these findings at the cellular level. The focus is on membrane and extracellular ENG and their influence on drug response and tumor cell behavior in non-small cell lung cancer (NSCLC) cells.</p><p><strong>Methods: </strong>The correlation between ENG expression and pemetrexed-induced cytotoxicity in eight human non-squamous subtype NSCLC cell lines was analyzed. ENG in A549 and H1975 cells was knocked down using shRNA. MTT assay, cell cycle assay, western blot analysis, and boyden chamber assay were used to detect the effect of ENG on pemetrexed-induced cytotoxicity, cell cycle distribution, and cell migration.</p><p><strong>Results: </strong>The expression of membrane ENG was positively correlated with pemetrexed-induced cytotoxicity in human NSCLC cells. Compared to pemetrexed-sensitive A549 cells, the A549/a400 (pemetrexed-resistant subline) cells exhibited a reduced accumulation of cells in the S phase, making them less susceptible to cell death. ENG knockdown also alleviated pemetrexed-induced S phase arrest and regulated G1/S phase-related proteins (p53, p21, CDK2, and Cyclin A). Additionally, co-treatment with recombinant ENG enhanced pemetrexed-induced migration inhibition in the sensitive cel1 line and cytotoxicity in the resistance cell line.</p><p><strong>Conclusion: </strong>The present results strengthened our prior clinical findings, showing that higher membrane ENG expression enhances pemetrexed-induced cytotoxicity and S phase arrest, which may involve the ENG-p21 pathway. Additionally, microenvironmental ENG enhanced the anti-migration of pemetrexed. These findings highlight the potential of ENG as a biomarker and therapeutic target, opening new avenues to improve the outcomes of non-squamous cell NSCLC treatment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"20"},"PeriodicalIF":2.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945186","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]PLB1004, a selective and irreversible EGFR-TKI in humans.","authors":"Donghui Liu, Qian Li, Shu Yan, Xinyue Zhang, Weiqiang Li, Feiyu Wang, Lei Gao, Fei Geng, Haiyan Zhou, Panpan Ye, Furong Zhao, Weizhe Xue, Peilong Zhang, Xingxing Diao, Wei Zhao","doi":"10.1007/s00280-024-04744-7","DOIUrl":"https://doi.org/10.1007/s00280-024-04744-7","url":null,"abstract":"<p><strong>Purpose: </strong>PLB1004, developed by Beijing Avistone Biotechnology Co., Ltd., is a safe, highly selective, and efficient irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) employed in treating non-small-cell-lung-cancer (NSCLC). This study investigated its pharmacokinetics, mass balance, and metabolism in 6 healthy Chinese male subjects treated with 160 mg (70 µCi) [¹⁴C]PLB1004.</p><p><strong>Methods: </strong>Following drug administration, samples of blood, urine and feces were collected for quantitative determination of total radioactivity and metabolites were identified through radioactivity detection coupled with UHPLC-MS/MS.</p><p><strong>Results: </strong>Following drug administration, the median radioactive T_max was 4.17 h in plasma, with the average t_1/2 of PLB1004-related components in plasma of approximately 54.3 h. Over 264 h post-administration, the average cumulative excretion among the six subjects was 95.01% of the administered dose, with 84.71% and 10.30% excreted in feces and urine, respectively. Nine metabolites were characterized and identified and the parent drug PLB1004 was detected in plasma, urine, and feces. Among these metabolites, M689 was the most prevalent one in plasma, urine, and feces, constituting 25.37% of the total plasma radioactivity, and 55.88% and 1.73% of the administrated dose in feces and urine, respectively.</p><p><strong>Conclusion: </strong>Fecal excretion emerged as PLB1004 excretion route, while urinary excretion via the kidneys served as the secondary route. The primarily metabolic pathways are oxidation, demethylation, dehydrogenation, and cysteine conjugation in humans.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"19"},"PeriodicalIF":2.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945188","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":"Landscape analysis of adverse events and dose intensity for FDA approved oncology small molecules.","authors":"Keagan P Collins, Donghua Yin, Yazdi K Pithavala, Rajendar K Mittapalli","doi":"10.1007/s00280-024-04721-0","DOIUrl":"10.1007/s00280-024-04721-0","url":null,"abstract":"<p><p>As development of new oncology small molecule therapies is focused mainly on molecularly targeted agents, the dose selection paradigm has shifted from the maximum tolerated dose (MTD)-based approach traditionally utilized with cytotoxic drugs towards determining an optimal dose with long-term tolerability while maintaining efficacy. To assess overall tolerability in recently approved oncology small molecules, we surveyed 54 compounds approved by the FDA since March 2017 with respect to dose intensity, dose modifications, and treatment emergent adverse events (TEAEs). Of the 54 new molecular entities surveyed, only 15 were approved at a label dose equal to the MTD (Label Dose = MTD). Compared to compounds where the label dose was less than the MTD, compounds where the Label Dose = MTD reported overall lower dose intensity and higher dose modifications due to adverse events, though treatment discontinuations due to adverse events were similar. A post-marketing requirement (PMR) for dose optimization was issued for 7 compounds in the dataset, of which 3 were at the Label Dose = MTD. None of these 7 compounds reported a positive exposure-response relationship in efficacy and only 4 reported an exposure-response in safety events. Overall, dose intensity was lower, and incidence of dose modifications, discontinuations, and Grade ≥ 3 TEAEs were higher in compounds issued a PMR vs. the latter. This analysis suggests that while recently approved oncology small molecules have a reasonable relative dose intensity (RDI), the higher incidence of Grade ≥ 3 TEAEs and dose modifications where Label Dose = MTD highlight the continuing need for dose optimization while developing oncology therapeutics.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"17"},"PeriodicalIF":2.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926606","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":"Nanotechnology and nanobots unleashed: pioneering a new era in gynecological cancer management - a comprehensive review.","authors":"Naina Kumar, Mishu Mangla","doi":"10.1007/s00280-024-04747-4","DOIUrl":"https://doi.org/10.1007/s00280-024-04747-4","url":null,"abstract":"<p><strong>Introduction: </strong>Gynecological cancers, such as ovarian, cervical, and endometrial malignancies, are notoriously challenging due to their intricate biology and the critical need for precise diagnostic and therapeutic approaches. In recent years, groundbreaking advances in nanotechnology and nanobots have emerged as game-changers in this arena, offering the promise of a new paradigm in cancer management. This comprehensive review delves into the revolutionary potential of these technologies, showcasing their ability to transform the landscape of gynecological oncology.</p><p><strong>Methodology: </strong>A systematic literature search spanning from March 2005 to August 2024 was conducted using major databases such as PubMed, Google Scholar, and Scopus. Keywords included \"nanotechnology,\" \"nanobots,\" \"gynecological cancers,\" \"ovarian cancer,\" \"cervical cancer,\" and \"endometrial cancer.\" Relevant articles published in English were selected based on their focus on nanotechnology and nanobots in the diagnosis, treatment, and management of gynecological cancers. The findings were synthesized to present a coherent overview of how nanotechnology and nanobots are reshaping gynecological cancer management. The review highlights key innovations, current applications, and future directions for research and clinical implementation.</p><p><strong>Conclusion: </strong>The integration of nanotechnology and nanobots in gynecological cancer management represents a groundbreaking shift in the field. Recent advancements in nanoscale materials and robotic technology offer unprecedented opportunities for precision diagnosis, targeted drug delivery, and innovative therapeutic approaches. Despite promising developments, challenges such as biocompatibility, safety, and regulatory issues remain. Continued research and clinical trials are essential to overcome these hurdles and fully realize the potential of nanotechnology and nanobots.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"18"},"PeriodicalIF":2.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926741","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":"DPYD genotype should be extended to rare variants: report on two cases of phenotype / genotype discrepancy.","authors":"Paul Vilquin, Yves Medard, Fabienne Thomas, Lauriane Goldwirt, Luis Teixeira, Samia Mourah, Evelyne Jacqz-Aigrain","doi":"10.1007/s00280-024-04738-5","DOIUrl":"https://doi.org/10.1007/s00280-024-04738-5","url":null,"abstract":"<p><p>The enzyme dihydropyrimidine dehydrogenase (DPD) is the primary catabolic pathway of fluoropyrimidines including 5 fluorouracil (5FU) and capecitabine. Cases of lethal toxicity have been reported in cancer patients with complete DPD deficiency receiving standard dose of 5FU or capecitabine. DPD is encoded by the pharmacogene DPYD in which more than 200 variants have been identified. Different approaches have been developed for screening DPD-deficiency, including DPYD genotyping and phenotyping. Plasma uracil ([U]) and dihydrouracil ([UH₂]) concentrations are routinely used as surrogate markers for systemic DPD activity: [U] ≥ 16 ng/ml and < 150 ng/ml, and [U] ≥ 150 ng/mL indicate partial and complete DPD deficient phenotype, respectively, while values of 5 or 10 for [UH2]/([U] ratio are often cited. Four clinically relevant DPYD defective variants (DPYD*13, DPYD*2A, p.Asp949Val and haplotype B3), are targeted in genetic testing via PCR. In practice, pretreatment [U], alone or combined with these 4 recommended DPYD alleles guides individual dosage selection, though this approach has limitations. This is illustrated by two cases showing discrepancy between DPD deficient phenotype and normal standard genotype. In these two cases, DPYD exome sequencing with Next Generation Sequencing identified rare inactive variants, establishing concordance between phenotype and genotype. In patient 1, [U] levels of 21.1 and 25.5 ng/mL, indicated partial deficiency though the targeted genotype was normal and 5FU dose was adjusted based on the phenotype. In patient 2, [U] levels of 16.2 and 15.2 ng/mL were near the 16 ng/ml threshold. With a normal genotype, he as considered non-deficient as targeted genotype was normal and the standard dose was administered. These two cases underscore the need to pair DPD phenotyping with whole DPYD gene sequencing, due to the frequent discrepancies between these pharmacogenetic tools, the burden of rare variants and ethnic differences in variant frequencies.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"16"},"PeriodicalIF":2.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913853","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":"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}