Cancer Chemotherapy and Pharmacology最新文献

{"title":"ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.","authors":"Palani Bharath, Sailakshmi Iyer, Ankitha Vadi Velu, D Thirumal Kumar","doi":"10.1007/s00280-026-04910-z","DOIUrl":"https://doi.org/10.1007/s00280-026-04910-z","url":null,"abstract":"<p><p>Anaplastic lymphoma kinase (ALK) gene rearrangements represent one of the well-characterized oncogenic drivers in non-small cell lung cancer (NSCLC), with the EML4-ALK fusion being the most common and clinically significant rearrangement. ALK inhibitors, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib has significantly improved clinical outcomes in ALK-rearranged NSCLC patients. However, the emergence of drug resistance remains inevitable which is mediated by either on-target mechanisms or off-target mechanisms. Mutations in the kinase domain, particularly in the solvent-front and gatekeeper regions alter the conformation of the ATP-binding site, leading to reduced binding affinity of ALK inhibitors. Importantly, G1202R-associated compound mutations confer high-level resistance, thereby limiting the effectiveness of currently available TKIs and posing a significant challenge in the clinical settings. In addition to acquired secondary mutations, the presence of the EML4-ALK variant 3 further worsens the prognosis and increases the risk of metastasis. Moreover, even when ALK is inhibited, activation of bypass signaling pathways can promote tumor progression via off-target mechanisms. To overcome these resistance mechanisms, the development of novel therapeutic strategies are required. By integrating structural biology, mutation evolution patterns, and emerging therapeutic approaches, this review underscores the need for next-generation inhibitors to overcome resistance and improve long-term outcomes in patients with ALK-positive NSCLC.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344017","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":"Central nervous system penetration of imatinib in acute lymphoblastic leukemia: Pharmacokinetic analysis and clinical implications.","authors":"Anna Sofie Buhl Rasmussen, Cecilie Utke Rank, Ib Jarle Christensen, Allan Weimann, Kasper Hansen, Maria Thastrup, Tianwu Yang, Trine Meldgaard Lund, Hilde Skuterud Wik, Hartmut Vogt, Ulrika Norén-Nyström, Goda Vaitkeviciene, Birgitte Klug Albertsen, Peder Skov Wehner, Bodil Als-Nielsen, Christen Lykkegaard Andersen, Kim Dalhoff, Kjeld Schmiegelow","doi":"10.1007/s00280-026-04914-9","DOIUrl":"10.1007/s00280-026-04914-9","url":null,"abstract":"<p><strong>Purpose: </strong>Tyrosine kinase inhibitors (TKIs) have improved outcomes in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and are increasingly incorporated into treatment protocols of Philadelphia chromosome-like (Ph-like, ABL-class) ALL. However, central nervous system (CNS) relapse remains a significant challenge. Imatinib, a first-generation TKI, demonstrates limited CNS penetration in adults, yet data in children are sparse.</p><p><strong>Methods: </strong>This prospective, multicenter study investigated cerebrospinal fluid (CSF) and matched plasma concentrations of imatinib and its primary bioactive metabolite (N-desmethyl-imatinib) in children and young adults with Ph + or Ph-like (ABL-class) ALL. Plasma and CSF samples were analyzed with liquid chromatography tandem mass spectrometry (LC-MS/MS). Linear mixed-effects models were used to assess concentrations across compartments and over time.</p><p><strong>Results: </strong>Between January 2023 and June 2025, 32 paired plasma and CSF samples were collected from ten patients (range 1-8 samples/patient; median: 3). In total, 78% of plasma imatinib concentrations were above 1,000 ng/mL. On average, plasma imatinib concentrations were 189-fold higher than in CSF (geometric mean ratio, 95% CI: 142-249, p < 0.001), which was even more profound for N-desmethyl-imatinib (geometric mean ratio 273, 95% CI: 218-339, p < 0.001). The highest measured CSF-imatinib concentration was 63 ng/mL. During therapy, both plasma and CSF imatinib concentrations declined at an average of 0.32% per day (p < 0.001), resulting in stable CSF-to-plasma ratio over a median follow-up of 5.7 months (range: 0-14 months).</p><p><strong>Conclusion: </strong>The very low CSF concentrations support the rationale for alternative TKIs with improved CNS distribution in patients at risk of CNS relapse.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13279477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275756","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":"Severe Methotrexate toxicity after ectopic pregnancy: a case report managed with continuous renal replacement therapy.","authors":"Yuting Chao, Qimeng Liu, Aihua Li, Yan Zhang","doi":"10.1007/s00280-026-04909-6","DOIUrl":"https://doi.org/10.1007/s00280-026-04909-6","url":null,"abstract":"<p><p>Methotrexate (MTX) is a cornerstone non-surgical therapy for ectopic pregnancy, but its narrow therapeutic window necessitates strict dose verification to prevent toxicity. We report a case of severe MTX intoxication in a 31-year-old woman following salpingostomy, resulting from a dosing error. After receiving an excessive intramuscular dose, the patient developed severe gastrointestinal symptoms and acute kidney injury (AKI). Initial management included prompt leucovorin rescue, urine alkalinization, and intensive supportive care; however, renal dysfunction progressed with impaired MTX clearance. In the absence of glucarpidase, the patient was transferred to the intensive care unit (ICU) and treated with continuous renal replacement therapy (CRRT), which facilitated sustained MTX removal and was followed by gradual clinical and biochemical recovery. This case highlights the critical importance of dose verification in MTX administration and illustrates that, when conventional measures are insufficient and glucarpidase is unavailable, CRRT may serve as a viable salvage therapy for life-threatening MTX toxicity complicated by AKI.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257408","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":"Model-based meta-analysis of individual patient data for the characterization of intravenous 5-fluorouracil population pharmacokinetics.","authors":"Myriam Briki, Paul Thoueille, Markus Joerger, Etienne Chatelut, Marylise Sterle, Antonin Schmitt, Anna Dorothea Wagner, Thierry Buclin, Sandro Carrara, Monia Guidi","doi":"10.1007/s00280-026-04885-x","DOIUrl":"10.1007/s00280-026-04885-x","url":null,"abstract":"<p><strong>Purpose: </strong>The pharmacokinetics (PK) of 5-fluorouracil (5-FU) has been thoroughly studied over the past decades. Using an individual patient data model-based meta-analysis (IPD-MBMA) approach, this study aims to build a generalized model by combining IPD from multiple studies, investigating the role of lean body mass (LBM) in 5-FU PK, and exploring a model informed precision dosing (MIPD)-based approach for refining its therapeutic drug monitoring (TDM).</p><p><strong>Methods: </strong>Raw PK data from three 5-FU PK studies (726 patients, 2,332 plasma concentrations) were harmonized and grouped into one homogeneous dataset, preserving traceability to the original data source. An overall population PK (popPK) model for intravenous 5-FU was developed using nonlinear mixed-effects modeling (NONMEM).</p><p><strong>Results: </strong>A two-compartment model with both saturable (Michaelis-Menten elimination; V_max, K_m) and linear elimination (CL) best described 5-FU disposition, with a stratified error model to capture between-study differences. Body-surface area (BSA) significantly impacted CL, and V_max was 15% lower in women and decreased with age. In a parallel analysis, the sex effect on V_max was translated into an LBM effect, with metabolic capacity increasing with LBM. Based on a 12-cycle simulation, after 4 cycles of TDM-based dose adjustment, 95% of the patient should be optimally exposed in the context of colorectal cancer (area under the curve, AUC 20-29 mg∙h/L). A virtual MIPD-based approach predicted higher target attainment after one adjustment (70 - 68%) compared to classic TDM predictions (49-59%) in men and women, respectively. Finally, the administration of a bolus before the continuous infusion of 5-FU is not expected to materially affect its subsequent continuous infusion AUC.</p><p><strong>Conclusion: </strong>Aggregating IPD enables building more generalizable popPK models while accommodating study-specific residual variability; broader raw-data sharing would strengthen current evidence and reveal remaining gaps. For 5-FU, BSA dosing leaves substantial interpatient variability, so LBM-based and model-informed strategies, including a priori dosing and MIPD-assisted TDM, warrant prospective evaluation.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223385","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":"Fosnetupitant for long-delayed chemotherapy-induced nausea and vomiting in oxaliplatin-based regimens: a prospective observational study (LODEC-N).","authors":"Yohei Iimura, Hirotoshi Iihara, Takeshi Aoyama, Toshinobu Hayashi, Masaaki Ishibashi, Chieko Sasuga, Naoki Furukawa, Eri Anzai, Yuki Ijichi, Seiichiro Kuroda","doi":"10.1007/s00280-026-04912-x","DOIUrl":"10.1007/s00280-026-04912-x","url":null,"abstract":"<p><strong>Purpose: </strong>Although previous standard antiemetic trials evaluated chemotherapy-induced nausea and vomiting (CINV) up to 120 h, recent evidence suggests that symptoms can persist well beyond this timeframe. However, the preventive efficacy of a triplet regimen including fosnetupitant (FosNTP) during the long-delayed phase (120-336 h) remains unclear in patients undergoing moderately emetogenic chemotherapy. This study aimed to prospectively evaluate the efficacy of FosNTP in preventing CINV during this extended long-delayed window.</p><p><strong>Methods: </strong>This single-center, single-arm, prospective observational study recruited patients scheduled to receive oxaliplatin-based chemotherapy. The primary endpoint was the long-delayed (120-336 h) complete control (CC) rate. Key secondary endpoints included the long-delayed complete response (CR) rate and the overall (0-336 h) CC, CR, and total control (TC) rates. Relative risks for emetogenic events were assessed using a logistic regression model.</p><p><strong>Results: </strong>The analysis included 100 patients. Most eligible patients received CapeOX (oxaliplatin + capecitabine) (92.0%). The long-delayed CC rate was 76.3%. The long-delayed CR and TC rates were 84.7% and 75.4%, respectively. Risk factors for CINV in participants who did not achieve CC during the long-delayed phase included age (odds ratio 0.954 [95% confidence interval 0.909-0.998]), female sex (8.808 [2.446-41.992]), and history of motion sickness (5.050 [1.118-27.548]).</p><p><strong>Conclusion: </strong>The triplet regimen involving FosNTP showed promising results and potential utility for managing long-delayed CINV in patients receiving oxaliplatin-based chemotherapy. However, given the single-arm study design, further comparative trials are warranted to confirm these findings. Participants with high emetic risk factors-such as younger age, female sex, or a history of motion sickness-continued to experience suboptimal control. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: jRCT1030230130.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197373","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":"Evaluation of anticancer activity of beta glucan in non-alcoholic steatohepatitis associated hepatocellular carcinoma in rats.","authors":"Sonia Bisht, Sangeetha Gupta","doi":"10.1007/s00280-026-04908-7","DOIUrl":"10.1007/s00280-026-04908-7","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) arising from non-alcoholic steatohepatitis (NASH) represents a growing clinical challenge with limited therapeutic options. Despite known antioxidant and immunomodulatory properties, the role of beta-glucan in NASH-associated HCC remains insufficiently explored.</p><p><strong>Methods: </strong>HCC was experimentally induced in rats via a single intraperitoneal (i.p.) injection of diethylnitrosamine (DEN; 200 mg/kg), followed by repeated intraperitoneal administrations of thioacetamide (TAA; 300 mg/kg) thrice weekly for four weeks. Upon establishment of hepatic tumors, beta-glucan was administered orally (p.o.) at doses of 25, 50, and 75 mg/kg/day for eight consecutive weeks. Sorafenib (30 mg/kg/day; p.o.) was used as the reference standard. Key parameters, including serum biochemical markers, oxidative stress indicators, insulin-like growth factor-1 (IGF-1) levels, and histopathological alterations, were evaluated to assess therapeutic efficacy.</p><p><strong>Results: </strong>Administration of high-dose beta-glucan (75 mg/kg/day, p.o.) significantly ameliorated hepatic injury, as evidenced by reductions in serum ALT and AST levels, restoration of antioxidant balance (increased GSH and decreased MDA), downregulation of IGF-1 expression, and normalization of hepatic histoarchitecture, demonstrating effects comparable to sorafenib. The intermediate dose (50 mg/kg/day, p.o.) conferred moderate hepatoprotective and anticancer effects, whereas the low dose (25 mg/kg/day, p.o.) exhibited minimal efficacy, with no significant improvements in most evaluated parameters.</p><p><strong>Conclusion: </strong>Beta-glucan exhibits dose-dependent protective effects in a preclinical model of NASH-associated HCC, potentially mediated through antioxidant and growth factor-modulating mechanism. These findings warrant further molecular and clinical investigation.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155513","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":"Autophagy impairs the sensitivity of Ewing sarcoma cells to PARP inhibitors.","authors":"Julia Clausen, Daniela Kocher, Hauke M Schadwinkel, Sabine Becker, Till Milde, James F Beck, Jürgen Sonnemann","doi":"10.1007/s00280-026-04907-8","DOIUrl":"10.1007/s00280-026-04907-8","url":null,"abstract":"<p><strong>Purpose: </strong>PARP inhibitors (PARPi) proved effective in Ewing sarcoma cells in preclinical studies. In clinical evaluation, however, the PARPi olaparib failed to elicit substantial responses, suggesting an unknown mechanism of resistance to PARPi in Ewing sarcoma. Since autophagy has been identified as a PARPi resistance mechanism in other tumours, this study aimed at exploring the impact of autophagy on PARPi effectiveness in Ewing sarcoma cells.</p><p><strong>Methods: </strong>Effects of the PARPi olaparib and veliparib were assessed by flow cytometry in the Ewing sarcoma cell lines WE-68 and SK-ES-1. Autophagy levels were determined using the autophagosome tracer dye Cyto-ID, and cytotoxic effects were determined by the analysis of cell death and loss of mitochondrial membrane potential. Cyto-ID was used to separate cell populations into subpopulations with low, medium and high autophagy by flow cytometric cell sorting.</p><p><strong>Results: </strong>Olaparib and veliparib induced autophagy and cell death in parallel in WE-68 and SK-ES-1 cells. Induction of autophagy and cell death occurred at the same concentrations of both PARPi in both cell lines. Analysis of cells sorted according to autophagy levels revealed a clear association between PARPi effectiveness and autophagy level. The subpopulation of Ewing sarcoma cells with high autophagy responded significantly less to PARPi with cell death than the subpopulation with low autophagy.</p><p><strong>Conclusion: </strong>This study demonstrates that autophagy affects the anticancer activity of PARPi in Ewing sarcoma cells.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13221416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052865","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":"A randomized, open-label, two-way crossover clinical trial to evaluate the food effect on pharmacokinetics and safety of DHP107 in patients with advanced solid tumors: the FEEL study.","authors":"Erika Hitre, István Láng, Dénes Páll","doi":"10.1007/s00280-026-04887-9","DOIUrl":"10.1007/s00280-026-04887-9","url":null,"abstract":"<p><strong>Purpose: </strong>The phase 1, randomized, open-label, two-way crossover FEEL study assessed the effect of food on the pharmacokinetics of DHP107, an oral paclitaxel with a novel lipid formulation designed to be systemically absorbed without Cremophor EL, in patients with advanced solid tumors.</p><p><strong>Methods: </strong>Patients were randomized 1:1 to DHP107 (200 mg/m² orally twice daily on Days 1, 8, 15 every 28 days for two cycles) treatment sequences: fasted-fed (first DHP107 dose administered after overnight fast; n = 13) and fed-fasted (first DHP107 dose administered after a high-fat meal; n = 12). The primary objective was to evaluate the effect of food on DHP107 pharmacokinetics. The secondary objective was DHP107 safety; efficacy was also assessed (both in all patients regardless of dosing sequence).</p><p><strong>Results: </strong>Mean systemic exposures were similar for paclitaxel and its metabolites under fed and fasted conditions. Geometric mean ratios (fed:fasted) for paclitaxel were: maximum concentration (C_max), 101.00% (95% CI 91.93-110.95%); area under the curve (AUC_0-72), 102.92% (95% CI 95.04-111.45%); and AUC_0-inf 104.76% (95% CI 96.44-113.80%), meeting criteria for no food effect. Common adverse events across the study period included diarrhea (fasted-fed 61.5%; fed-fasted 41.7%), vomiting (fasted-fed 30.8%; fed-fasted 8.3%), and neutropenia (fasted-fed 23.1%; fed-fasted 16.7%). Two fed-fasted patients (16.7%) had partial responses and six had stable disease (50.0%); seven fasted-fed patients had stable disease (53.8%).</p><p><strong>Conclusion: </strong>This study suggests that the pharmacokinetics of DHP107 are unaffected by food and DHP107 can be taken with or without food.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov ID: NCT04675528; 107CS-7.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13221415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052914","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":"Antibody-drug conjugates in colorectal cancer: molecular design, preclinical advances, and translational challenges.","authors":"Md Arif Ansari, Md Abubakar, Mohd Mazharuddin Ansari, Nabeeha Koya, Janmejay Gupta, Maria Aazam, Sonali Sandeep Shinde, Sana Ahmed, Amita Rai, Krishna Murti, Biplab Pal, Sachchida Nand Rai, Palwinder Kaur, Smita Shenoy, Nitesh Kumar","doi":"10.1007/s00280-026-04906-9","DOIUrl":"10.1007/s00280-026-04906-9","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, largely because of tumor heterogeneity, therapeutic resistance, and the limited efficacy of existing targeted therapies in advanced disease. Antibody-drug conjugates (ADCs) have emerged as a promising class of targeted anticancer therapeutics that combine the specificity of monoclonal antibodies with the cytotoxic potency of highly active payloads, thereby enabling selective tumor cell killing while minimizing systemic toxicity. Although ADCs have demonstrated substantial clinical success in several solid and hematological malignancies, their translation to CRC has been relatively limited, underscoring the need for a focused evaluation of CRC-specific ADC development. This review provides a comprehensive and critical overview of recent advances in ADC design and preclinical development for CRC, with emphasis on molecular architecture, linker-payload chemistry, antigen selection, and pharmacological mechanisms of action. Key components of ADCs, including antibody formats, cleavable and noncleavable linkers, and cytotoxic payload classes such as auristatins, maytansinoids, duocarmycins, and topoisomerase inhibitors, are discussed in the context of optimizing the therapeutic index and tumor selectivity. Mechanistic aspects of ADC activity, including antigen-mediated internalization, intracellular trafficking, payload release, and the bystander effect, are highlighted for their relevance to heterogeneous CRC tumors. This review systematically summarizes emerging preclinical ADC candidates targeting CRC-associated antigens, including EGFR, CEACAM5, c-Met, RON, DDR1, GPR56, LGR5, Claudin-2, and CD98hc. Finally, key translational challenges-including antigen heterogeneity, limited internalization, and off-target toxicity-are discussed alongside future perspectives emphasizing biomarker-driven patient selection and rational ADC design.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13219184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041268","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":"Combinational studies of BOLD-100/KP1339 with established chemotherapeutics in gastrointestinal multicellular tumor spheroids.","authors":"Dominik Wenisch, Slavica Ždravac, Michael A Jakupec, Franz Jirsa, Bernhard K Keppler","doi":"10.1007/s00280-026-04902-z","DOIUrl":"10.1007/s00280-026-04902-z","url":null,"abstract":"<p><p>BOLD-100, a ruthenium(III) prodrug also known as KP1339, is currently under clinical investigation for its suitability as a co-therapeutic anticancer drug. Unlike platinum-based chemotherapeutics, it has unique non-DNA targets, mainly GRP78, an enzyme responsible for signaling related to protein folding in the ER. Inhibition of this key mediator of the \"unfolded protein response\" may lead to cell death eventually. The purpose of this study was to assess in vitro the impact of BOLD-100 combinations with oxaliplatin, 5-FU, cisplatin or SN38 in multicellular tumor spheroids (MCTSs) compared to single-drug treatments. Gastric (MKN45, NCI-N87) and colorectal cancer (HCT116, HT29) cell lines were chosen, corresponding to the clinical trial in which patients with tumors of these origins are being treated. Biological effects investigated in this study include cytotoxic activity, synergism/antagonism based on Chou and Talalay's algorithm, formation of reactive oxygen species (ROS) and induction of apoptosis and necrosis. Cytotoxicity tests showed vastly different chemosensitivities in MCTSs of the same tumor origin. In both tumor entities, partially synergistic effects were revealed when BOLD-100 was combined with the drugs mentioned above. The DCFH-DA assay suggested consistent increases of ROS levels after treatment with oxaliplatin and, with restrictions, its combination with BOLD-100. Apoptosis and necrosis were induced in the spheroid models by single-drug and combined treatment, with no hints at antagonism in the combination settings. In conclusion, these findings emphasize the potential of BOLD-100 for combination therapy of gastric and colorectal cancers.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986710","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}