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Usnic acid is a marker compound produced from numerous lichens (symbiotic association of mycobiont and phycobiont) possessing higher bioavailability, potent and selective against cancer cells. Usnic acid is an underutilized and well-documented anti-cancer compound from lichens and its activity is not yet documented against cervical cancer. The main aim of the present research is to screen the anti-cancer potential of usnic acid against cervical cancer target proteins. The drug-likeness validation of usnic acid shows nil violations against all drug-likeness rules when compared with all three screened anti-cancer standard drugs and shows some violation in drug likeness prediction. Further, ADMET screening reveals usnic acids shows effective pharmacokinetic profiles with good bioactivity scores, essential for drug delivery and metabolism. DFT analysis of usnic acid reveals less energy gap (-0.1184), hardness (0.0592 eV), and high softness (16.8918 eV) scores against three anti-cancer drug DFT scores. Molecular docking study shows usnic acid possesses excellent binding affinity with all the nine screened cervical cancer target proteins with docking scores ranging from -6.9 to -9.1 kcal/mol. Three anti-cancer drugs showed docking scores with a range of -5.2 to -8.4 kcal/mol. Further, four top-scored complexes were taken for molecular dynamic simulation study reveal that usnic acid complexes (1KTZ-usnic acid and 2BIM-usnic acid) possess good simulation trajectories with cervical cancer target proteins than the selected anti-cancer drugs.Communicated by Ramaswamy H. Sarma.

Introduction: Treatment with topotecan is standard-of-care therapy for relapsed small-cell lung cancer (SCLC). Both oral and intravenous administrations of topotecan have been extensively researched and are found to be equally effective with less adverse events in the oral group., Case Presentation: We report a case of a patient with SCLC, who had previously received oral topotecan, with radiological stable disease with no changes in tumor or metastasis diameter size after two administrations. Subsequently, this patient received intravenous topotecan instead of oral due to supply difficulties. After one administration of intravenous topotecan, we saw significant disease regression., Conclusion: This is to our knowledge the first reported case of better response of intravenous topotecan than oral topotecan. Multiple extrinsic (e.g., food, medication) factors were investigated but could not deliver an explanation., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

For the first time, a synthetic route for preparing lupane and oleanane derivatives with a hydrogenated furan ring as a cycle A of triterpene scaffold is described. Most of the synthesized compounds, furanoterpenoids and their synthetic intermediates, were non-toxic against the tested cancer and non-cancerous cell lines, and evinced significant inhibitory activity with IC 50 1.0-9.0 μM in the tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition test. Lupane derivatives - 1-oxime 7, 1,10-seco-hydroxynitrile 11 and furanoterpenoid 14 - were selected as those expected to be the most promising compounds. The results of molecular modeling evinced the strongest binding of compound 11 to the active site of Tdp1 compared to the reference drug. Simultaneously, only compound 11 at subtoxic concentration (10 μM) produced a synergetic effect on the topotecan activity against HeLa-V cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Purpose: To study the long-term efficacy of intravitreal topotecan (IVT) for vitreous seeds in eyes with retinoblastoma and risk factors for their recurrence., Design: Retrospective, non-comparative, interventional study., Participants: Ninety-one eyes of 90 patients with retinoblastoma treated between January 2013 and April 2019., Methods: Patients with recurrent or refractory vitreous seeds after completion of intravenous or intra-arterial chemotherapy were treated with IVT (30 μg/0.15 ml) by the safety-enhanced technique. The injection was repeated every 4 weeks until the regression of seeds. Patients with a minimum follow-up of 12 months were included in the analysis., Main Outcome Measures: Primary outcome measures were vitreous seed regression and eye salvage. Secondary outcomes were risk factors for vitreous seed recurrence after treatment with IVT, vision salvage, and complications of IVT., Results: The median age of the patients was 18 months, with most having group D (n = 58 [64%]) and group E (n = 26 [29%]) retinoblastoma. Vitreous seeds were refractory in 46 eyes (51%) and recurrent in 45 eyes (49%). A total of 317 IVT injections were administered, with the median being 3 injections. The median number of IVT injections required was 2.5 injections for dust, 3 injections for sphere, and 5 injections for cloud morphologic features. Recurrence of vitreous seeds after IVT was seen in 17 eyes (19%) at a mean follow-up of 7.9 months. At a mean follow-up 34 months, vitreous seed regression was achieved in 88 eyes (97%) and eye salvage was achieved in 77 eyes (85%). Older age (P = 0.018) and recurrence of retinal tumor (15/17 eyes; P < 0.01) significantly increased the risk of vitreous seed recurrence. Cataract was the most common complication seen in 17 eyes (9%)., Conclusions: Intravitreal topotecan at an every 3- to 4-week regimen is effective against both refractory and recurrent vitreous seeds. The vitreous seed morphologic features correspond to the number of injections required for regression. Increasing age and recurrence of retinal tumor increase the risk of vitreous seed recurrence after treatment with IVT., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Intraarterial chemotherapy (Ophthalmic Artery Chemosurgery/OAC) for retinoblastoma has transformed management of retinoblastoma worldwide since Pierre Gobin MD and I introduced it in 2006. Case reports, institutional series, meta-analyses, and randomized trials have validated its effectiveness and safety. It allows more eyes to be saved (at Memorial Sloan Kettering Cancer Center (MSKCC) as a result, we have gone from removing 96% of retinoblastoma eyes that presented with leukocoria (comparable to modern day International Classification "D" and "E" eyes) to saving 95% of these eyes with primary OAC management allows the majority of advanced intraocular eyes to be salvaged (both "D" and "E" eyes) prior to the chemoreduction era to saving 95% of these eyes with primary OAC management. OAC attains cures faster than intravenous protocols, has fewer systemic side effects, and is overall cheaper than intravenous approaches (because of the absence of side effects which are the main driver of cost in pediatric oncology). Unlike systemic chemotherapy no ports are needed (and no removal of ports for life threatening infections), it does not alter the immune system (so children can be immunized), it does not affect patient growth (and children who had received systemic chemotherapy catch up in growth during OAC), it does not affect hearing (which systemic Carboplatin does-especially in children <6 months of age), it eliminates the second cancers caused by radiation and systemic chemotherapy and does not compromise survival with all series showing patient survival >98%.

Metastasis is a major contributing factor that affects the prognosis of melanoma patients. Nevertheless, the underlying molecular mechanisms involved in melanoma metastasis are not yet entirely understood. Here, we identified ubiquitin-specific protease 22 (USP22) as a pro-oncogenic protein in melanoma through screening the survival profiles of 52 ubiquitin-specific proteases (USPs). USP22 demonstrates a strong association with poor clinical outcomes and is significantly overexpressed in melanoma. Ablation of USP22 expression remarkably attenuates melanoma migration, invasion, and epithelial-mesenchymal transition in vitro and suppresses melanoma metastasis in vivo. Mechanistically, USP22 controls melanoma metastasis through the SIRT1/PTEN/PI3K pathway. In addition, we conducted an United States Food and Drug Administration-approved drug library screening and identified topotecan as a clinically applicable USP22-targeting molecule by promoting proteasomal degradation of USP22. Finally, we found that both pharmacological and genetic silence of USP22 sensitize RSL3-induced ferroptosis through suppressing the PI3K/Akt/mTOR pathway and its downstream SCD, and ferroptosis inhibitor could partly rescued the decreased lung metastasis by topotecan in vivo. Overall, our findings reveal a prometastatic role of USP22 and identify topotecan as a potent USP22-targeting drug to limit melanoma metastasis., Competing Interests: The authors have no relevant financial or nonfinancial interests to disclose., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Background: Small cell lung cancer (SCLC) presents considerable challenges regarding the availability of second-line treatment options, which remain limited. The paucity of effective therapeutic choices at this setting emphasizes the urgent requirement for rigorous research and investigation into novel treatment strategies. To address this clinical gap, the current study aimed to compare the efficacy and safety of anlotinib with the standard second-line treatment, topotecan, in patients with relapsed SCLC., Methods: This retrospective collected data from SCLC patients who received either anlotinib or topotecan as second-line treatment. The primary endpoints were progression-free survival (PFS), while the secondary endpoints included the overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety assessment., Results: The study included 46 SCLC patients, with 20 receiving anlotinib and 26 receiving topotecan as second-line treatment. The anlotinib group showed a significantly longer median PFS compared to the topotecan group [5.6 vs. 2.2 months; hazard ratio (HR) =0.50; 95% confidence interval (CI): 0.27-0.92; P=0.02]. However, there was no statistically significant difference in OS between the two groups (9.1 vs. 7.7 months; HR =0.88; 95% CI: 0.46-1.70; P=0.71). The ORRs were 20.0% and 7.7% (P=0.48), and the DCRs were 70.0% and 23.1% (P=0.007) for the anlotinib and topotecan groups, respectively. Treatment-related adverse events (TRAEs) occurred in 13 patients (65.0%) in the anlotinib group and 20 (76.9%) in the topotecan group (P=0.49)., Conclusions: Anlotinib shows the potential to extend PFS and manageable adverse events (AEs) compared to topotecan in the second-line setting for relapsed SCLC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-274/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Background: Glioblastoma is characterized by high aggressiveness, frequent recurrence, and poor prognosis. Histone acetylation-associated genes have been implicated in its occurrence and development, yet their predictive ability in glioblastoma prognosis remains unclear., Results: This study constructs a histone acetylation risk model using Cox and LASSO regression analyses to evaluate glioblastoma prognosis. We assessed the model's prognostic ability with univariate and multivariate Cox regression analyses. Additionally, immune infiltration was evaluated using ESTIMATE and TIMER algorithms, and the SubMAP algorithm was utilized to predict responses to CTLA4 inhibitor. Multiple drug databases were applied to assess drug sensitivity in high- and low-risk groups. Our results indicate that the histone acetylation risk model is independent and reliable in predicting prognosis., Conclusions: Low-risk patients showed higher immune activity and longer overall survival, suggesting anti-CTLA4 immunotherapy suitability, while high-risk patients might benefit more from chemotherapy. This model could guide personalized therapy selection for glioblastoma patients., (© 2024. The Author(s).)

Background: Small-cell lung cancer (SCLC) is a highly aggressive tumor, and overall survival (OS) remains poor despite intensive efforts to develop new treatment strategies. In second line, topotecan is the only approved drug, with a median OS of 5.9 months. However, real-world SCLC patients are often in worse condition and harbor more comorbidities than study populations. Therefore, the real-world performance of topotecan may differ from that seen in studies. Here, we analyzed outcomes of SCLC patients receiving topotecan and identified predictive and prognostic markers., Patients and Methods: We retrospectively analyzed 44 consecutive SCLC patients receiving topotecan between 2015 and 2022. We analyzed baseline characteristics (age, ECOG-PS, topotecan cycles, and dosage) and pre-treatment blood values (LDH, CRP, sodium) as well as prognostic scores (neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), Glasgow Prognostic Score, prognostic nutritional score, systemic inflammation index (SII), and the prognostic index) extracted from electronic patients' charts to identify predictive and prognostic markers., Results: In our cohort, mPFS and mOS were only 1.9 and 5.6 months, respectively. Gender, ECOG-PS, active brain metastases, NLR, GPS, PNI, and SII significantly influenced PFS and OS in univariate analysis. ECOG-PS ( p > 0.001), active brain metastases ( p = 0.001), and SII ( p = 0.008) were significant independent prognostic variables in a multivariate COX regression model. Selecting patients by these three markers achieved an mPFS of 5.7 months and thus increased the mPFS three-fold. Patients not meeting all criteria had an mPFS of 1.8 months ( p = 0.006). Patients identified by prognostic markers had an mOS of 9.1 months ( p = 0.002)., Conclusions: The efficacy of topotecan in SCLC real-world patients is poor, indicating that many patients were treated without any benefit. Easy-to-obtain markers can predict response and treatment efficacy and should therefore be validated in larger cohorts to identify patients who are more likely to benefit from topotecan.

Gold nanomaterials have been widely explored in electrochemical sensors due to their high catalytic property and good stability in multi-medium. In this paper, the reproducibility of the signal among batches of gold nanorods (AuNRs)-modified electrodes was investigated to improve the data stabilization and repeatability. Ordered and random self-assembled AuNRs-modified electrodes were used as electrochemical sensors for the simultaneous determination of dopamine (DA) and topotecan (TPC), with the aim of obtaining an improved signal stability in batches of electrodes and realizing the simultaneous determination of both substances. The morphology and structure of the assemblies were analyzed and characterized by UV-Vis spectra, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray powder diffraction (XRD). Electrochemical studies showed that the ordered AuNRs/ITO electrodes have excellent signal reproducibility among several individuals due to the homogeneous mass transfer in the ordered arrangement of the AuNRs. Under the optimized conditions, the simultaneous detection results of DA and TPC showed good linearity in the ranges 1.75-45 μM and 1.5-40 μM, and the detection limits of DA and TPC were 0.06 μM and 0.17 μM, respectively. The results showed that the prepared ordered AuNR/ITO electrode had high sensitivity, long-term stability, and reproducibility for the simultaneous determination of DA and TPC, and it was expected to be applicable for real sample testing., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Organic anion transporter 3 (OAT3), expressed at the basolateral membrane of kidney proximal tubule cells, facilitates the elimination of numerous metabolites, environmental toxins, and clinically important drugs. An earlier investigation from our laboratory revealed that OAT3 expression and transport activity can be upregulated by SUMOylation, a post-translational modification that covalently conjugates SUMO molecules to substrate proteins. Topotecan is a semi-synthetic derivative of the herbal extract camptothecin, approved by the FDA to treat several types of cancer. Ginkgolic acid (GA) is one of the major components in the extract of Ginkgo biloba leaves that has long been used in food supplements for preventing dementia, high blood pressure, and supporting stroke recovery. Both topotecan and GA have been shown to affect protein SUMOylation. In the current study, we tested our hypothesis that topotecan and GA may regulate OAT3 SUMOylation, expression, and transport function. Our data show that the treatment of OAT3-expressing cells with topotecan or GA significantly decreases the SUMOylation of OAT3 by 50% and 75%, respectively. The same treatment also led to substantial reductions in OAT3 expression and the OAT3-mediated transport of estrone sulfate, a prototypical substrate. Such reductions in cell surface expression of OAT3 correlated well with an increased rate of OAT3 degradation. Mechanistically, we discovered that topotecan enhanced the association between OAT3 and the SUMO-specific protease SENP2, a deSUMOylation enzyme, which contributed to the significant decrease in OAT3 SUMOylation. In conclusion, this study unveiled a novel role of topotecan and GA in inhibiting OAT3 expression and transport activity and accelerating OAT3 degradation by suppressing OAT3 SUMOylation. During comorbidity therapies, the use of topotecan or Ginkgo biloba extract could potentially decrease the transport activity of OAT3 in the kidneys, which will in turn affect the therapeutic efficacy and toxicity of many other drugs that are substrates for the transporter.

In this work, UiO-66-NH 2 /GO nanocomposite was prepared using a simple solvothermal technique, and its structure and morphology were characterized using field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), and X-ray diffraction (XRD). An enhanced electrochemical sensor for the detection of epirubicin (EP) was proposed, which utilized a UiO-66-NH 2 /GO nanocomposite-modified screen-printed graphite electrode (UiO-66-NH 2 /GO/SPGE). The prepared UiO-66-NH 2 /GO nanocomposite improved the electrochemical performance of the SPGE towards the redox reaction of EP. Under optimized experimental conditions, this sensor demonstrates a remarkable limit of detection (LOD) of 0.003 µM and a linear dynamic range from 0.008 to 200.0 µM, providing a highly capable platform for sensing EP. Furthermore, the simultaneous electro-catalytic oxidation of EP and topotecan (TP) was investigated at the UiO-66-NH 2 /GO/SPGE surface utilizing differential pulse voltammetry (DPV). DPV measurements revealed the presence of two distinct oxidation peaks of EP and TP, with a peak potential separation of 200 mV. Finally, the UiO-66-NH 2 /GO/SPGE sensor was successfully utilized for the quantitative analysis of EP and TP in pharmaceutical injection, yielding highly satisfactory results.

Topotecan administered intraperitoneally at single doses of 0.25, 0.5, and 1 mg/kg induced chromosomal aberrations in bone marrow cells of F 1 (CBA×C57BL/6) hybrid mice in a dose-dependent manner. A tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitor, an usnic acid derivative OL9-116 was inactive in a dose range of 20-240 mg/kg, but enhanced the cytogenetic effect of topotecan (0.25 mg/kg) at a dose of 40 mg/kg (per os). The TDP1 inhibitor, a coumarin derivative TX-2552 (at doses of 20, 40, 80, and 160 mg/kg per os), increased the level of aberrant metaphases induced by topotecan (0.25 mg/kg) by 2.1-2.6 times, but was inactive at a dose of 10 mg/kg. The results indicate that TDP1 inhibitors enhance the clastogenic activity of topotecan in mouse bone marrow cells in vivo and are characterized by different dose profiles of the co-mutagenic effects., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen., Methods: We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration-time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model., Results: FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage., Conclusions: Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens., (© 2024. The Author(s).)

Background: Before the era of immunotherapies and antibody-drug conjugates, there were limited chemotherapeutic options for patients with recurrent and metastatic cervical cancer. Combination therapies with cisplatin have shown some superiority over monotherapy. This study examined platinum-free treatment regimens, comparing a combination of topotecan and paclitaxel (TP) with topotecan and cisplatin (TC) in patients with recurrent or metastatic cervical cancer, with or without prior platinum-based treatment., Methods: The AGO-Zervix-1 Study (NCT01405235) is a prospective, randomized phase III study in which patients were randomly assigned at a 1:1 ratio to treatment within the control arm with topotecan (0.75 mg/m 2 ) on days 1-3 and cisplatin (50 mg/m 2 ) on day 1 every 3 weeks and in the study arm topotecan (1.75 mg/m 2 ) and paclitaxel (70 mg/m 2 ) on days 1, 8, and 15 every 4 weeks or treatment. The primary study aim was overall survival; progression-free survival, toxicity, and quality of life were secondary aims. The interim and final analysis is here reported after recruitment of 173 of 312 planned patients., Results: Median overall survival in the TP arm was 9.6 months, compared with 12.0 months in the TC arm (log-rank test, P = 0.33). Median progression-free survival rates were 4.4 months with TP and 4.2 months with TC (log-rank test, P = 0.47). Leukopenia and nausea/vomiting were more frequent in the cisplatin-containing arm. Otherwise, toxicity profiles were comparable. There were no differences in FACT-G-assessed quality of life., Conclusion: Platinum-based combination chemotherapy remains the standard of care chemotherapy regimen for patients with recurrent or metastatic cervical cancer., Competing Interests: Declaration of competing interest P.G. has received honoraria from Novartis, MSD, and AstraZeneca. I.V. reports Consulting fees from Agenus, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, GSK, Immunogen, Karyopharm, Mersana, MSD, Molecular Partners, Novocure, Novartis, Oncoinvent, Regeneron, Seagen, Verastem Oncology, Zai Lab, Zentalis. P.H. declares honoraria from Amgen, Astra Zeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Mersana, Exscientia, Advisory Board participations from Astra Zeneca, Roche, GSK, Clovis, Immunogen, MSD, Miltenyi, Novartis, Eisai and Research Funding (Inst) from Astra Zeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Seagen, Clovis, Novartis. The other authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: Osteosarcoma at an advanced stage has a poor outcome, and novel targeted therapies are needed, especially for metastatic disease. Bromodomain inhibitors (BETi) are epigenetic modulators that broadly impair the expression of oncogenic proteins and exert antitumor effects. BETi can be combined with chemotherapeutics to increase therapeutic responses with superior effects in the form of proteolysis targeting chimeras (PROTACs) that degrade proteins of interest (POI) in multiple cycles. This work aimed to investigate the efficacy of BETi, such as JQ1, dBET57, and MZ1 PROTACs in combination with cytotoxic drugs against osteosarcoma cell lines., Materials and Methods: Chemosensitivity of the osteosarcoma cell lines HOS, Saos-2, MG-63, and G292 were tested with BET-directed agents alone or in combination with cytotoxic drugs comprising cisplatin, doxorubicin, topotecan, and gemcitabine using cell viability assays., Results: The BET degraders exhibited highest toxicity to HOS cells and showed synergistic activity in combination with the chemotherapeutics, except for the degrader - topotecan/gemcitabine combinations. Highest synergy between BET agents and chemotherapeutics were found for the more chemoresistant Saos-2 cells and potentiation of toxicity in MG-63 cells for the BET agents - doxorubicin combinations and the MZ1-topotecan pair. HOS and Saos-2 cell lines had reduced protein expression of AXL, BCL-X, e-cadherin, CAIX, EpCAM, ErbB2, and vimentin in response to JQ1, MZ1, and BET57., Conclusion: The study suggests that the application of novel BET PROTACs in combination with chemotherapeutics could represent a new therapeutic option to improve the therapy of osteosarcomas. First orally available PROTACs have reached clinical trials., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: This report focuses on lurbinectedin activity and safety in a subgroup of small cell lung cancer (SCLC) patients from a Basket phase 2 study (Trigo et al. Lancet Oncology 2020;21:645-654) with chemotherapy-free interval (CTFI) ≥ 30 days. This pre-planned analysis was requested for obtaining regulatory approval of lurbinectedin in Switzerland., Materials and Methods: Patients with extensive-stage SCLC, no central nervous system (CNS) metastases, and disease progression after platinum-containing therapy were included. Topotecan data from a contemporary, randomized, controlled phase 3 study (ATLANTIS) were used as indirect external control in a matched patient population (n = 98 patients)., Results: Lurbinectedin showed a statistically significant higher overall response rate (ORR) by investigator assessment (IA) compared to topotecan subgroup (41.0 % vs. 25.5 %; p = 0.0382); higher ORR by Independent Review Committee (IRC) (33.7 % vs. 25.5 %); longer median duration of response (IA: 5.3 vs. 3.9 months; IRC: 5.1 vs. 4.3 months), and longer median overall survival (10.2 vs. 7.6 months). Grade ≥ 3 hematological abnormalities were remarkably lower with lurbinectedin: anemia 12.0 % vs. 54.1 %; leukopenia 30.1 % vs. 68.4 %; neutropenia 47.0 % vs. 75.5 %, and thrombocytopenia 6.0 % vs. 52.0 %. Febrile neutropenia was observed at a higher incidence with topotecan (6.1 % vs. 2.4 % with lurbinectedin) despite that the use of growth-colony stimulating factors was mandatory with topotecan., Conclusion: With the limitations of an indirect comparison, however using recent and comparable SCLC datasets, this post hoc analysis shows that SCLC patients with CTFI ≥ 30 days and no CNS metastases have a positive benefit/risk ratio with lurbinectedin, superior to that observed with topotecan., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Solange Peters received education grants,provided consultation, attended advisory boards and/or provided lecturesfor the following organizations, from whom she received honoraria (all fees to institution): consultation/advisory role: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen,Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, MJH Life Sciences, Nykode Therapeutics, Novartis, Novocure, OncologyEducation, Pharma Mar, Promontory Therapeutics, Peerview, Pfizer, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda; Board of Director position: Galenica; Talk in a company’s organized public event: AiCME, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, GSK, Illumina, Imedex, Ipsen, Medscape, Merck Sharp and Dohme, Mirati, MJH Life Sciences, Novartis, Peerview, Pfizer, Roche/Genentech, RTP, Sanofi, Taked; receipt of grants/research supports: Principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, Arcus, AstraZeneca, Beigene, Bristol-Myers Squibb, GSK, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, Seattle Genetics. Dr. José Trigo participated on data monitoring and safety board for this study. Dr. Alejandro Navarro received consulting fees from Boehringher Ingelheim,Takeda, Bristol Myers Squibb Foundation, Adium Pharma, Pfizer, Eczacibasi and Amgen; received payment for speaker’s bureau from Roche and AstraZeneca Spain; received payment for expert testimony from Oryzon Genomics, Medsir and Hengenix; and had support for attending meetings and/or travel from Boehringer Ingelheim, Pfizer and Roche. Dr. Luis Paz-Ares had grants or contracts from MSD, Astrazeneca, Pfize and BMS; received consulting fees from Lilly, MSD, Roche, Pharmamar, Merck, Astrazeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda and Daichii Sankyo; and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astrazeneca, Janssen, Merck and Mirati. Dr. Christian Gohé received consulting fees from Boehringher, AstraZeneca, Novartis, Sanofi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Boehringher and AstraZeneca; payment for expert testimony from AstraZeneca; and had support for attending meetings and/or travel from Daichi. Drs. José Antonio López-Vilariño, Cristian Fernandez, Carmen Kahatt, Vicente Alfaro, Antonio Nieto and Ali Zeaiter received personal fees for salary as full time employees and stock ownership from Pharma Mar. Dr. Vivek Subbiah participated in Advisory Boards of Jazz Pharmaceuticals, Loxo Oncology/Eli Lilly, Regeneron, Relay Therapeutics, Pfizer, Roche, ABBVIE, Novartis, Bayer, Aadi Biosciences, Illumina, and Labcorp; and received payment for educational events from Clinical Care Options, LLC. Other authors declared no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives: tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7 ) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer.

DNA topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention. Human DNA Ligase 1 (hLig I), recognized primarily for its role in DNA replication and repair of DNA breaks, intriguingly exhibits a DNA relaxation activity akin to Topo 1. This raised the hypothesis that hLig I might compensate for Topo 1 inhibition, contributing to resistance against Topo 1 inhibitors. To explore this hypothesis, we assessed the efficacy of hLig I inhibition alone and in combination with Topo 1 in cancer cells. As anticipated, the overexpression of hLig I was observed after Topo 1 inhibition in colorectal cancer cells, affirming our hypothesis. Previously identified as an inhibitor of hLig I's DNA relaxation activity, compound 27 (C 27), when combined with Topotecan, demonstrated a synergistic antiproliferative effect on colorectal cancer cells. Notably, cells with downregulated hLig I ( via siRNA, inhibitors, or genetic manipulation) exhibited significantly heightened sensitivity to Topotecan. This observation strongly supports the concept that hLig I contribute to resistance against clinically relevant Topo 1 inhibitors in colorectal cancers. In conclusion, our findings offer evidence for the synergistic impact of combining hLig I inhibitors with Topotecan in the treatment of colorectal cancers, providing a promising strategy to overcome resistance to Topo 1 inhibitors.Communicated by Ramaswamy H. Sarma.

Purpose: Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma., Methods: Oral cabozantinib (25 mg/m 2 ) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75 mg/m 2 ) and cyclophosphamide (250 mg/m 2 ) were administered intravenously (IV) on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation., Results: Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (seven with Ewing sarcoma; five with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis, grade 3 transaminitis, and prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease., Conclusions: The recommended phase 2 doses and schedules for this combination are topotecan 0.75 mg/m 2 IV days 1-5, cyclophosphamide 250 mg/m 2 IV days 1-5, and cabozantinib 25 mg/m 2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity, while allowing for potential disease control., (© 2023 Wiley Periodicals LLC.)

The intracellular delivery of the drug to the solid tumor is a major challenge in the treatment of solid tumors. This project aims to increase cytosolic drug delivery using the endosomal escape of drugs. Topotecan (TPT) and capsaicin were used for the treatment of solid tumors. The pH-dependent conversion of active lactone form to inactive carboxylic form is a major problem of TPT that limits its therapeutic use. Liposomal encapsulation of TPT improved the stability of active lactone form and increased the therapeutic efficacy of TPT. Endosomal degradation of liposomes may reduce the content in the target cells. To solve these problems, pH-sensitive liposomes (pSLPs) were developed which improved the intracellular drug delivery by the endosomal escape of drugs. The liposomes (LPs) bearing the drug(s) were prepared using the cast film method and optimized for various formulation and process variables using the Design-Expert 7 software by employing the Box-Behnken design (BBD). The developed hyaluronic acid (HA)-conjugated pSLPs (HA-pSLPs) displayed a vesicle size of 166.5 ± 2.31 nm, zeta potential - 30.53 ± 0.91, and entrapment efficiency of 44.39 ± 1.78%, and 73.48 ± 2.15% for TPT and CAP, respectively. HA-pSLPs displayed better cytotoxicity in comparison to free drugs either single or in combination on the MCF-7 cell line. The apoptosis and cellular uptake of HA-pSLPs were increased ⁓ 4.45-fold and ⁓ 6.95-fold as compared to unconjugated pSLPs, respectively. The pharmacokinetic studies in Balb/c mice demonstrated that HA-pSLPs increased the half-life, MRT, and AUC in comparison to the free drug solution. The HA-pSLPs formulation has shown remarkable tumor regression as compared to PpSLPs, pSLPs, and free drug combinations. These results demonstrated that TPT- and CAP-loaded HA-pSLPs offer a potential platform for targeted drug delivery to solid tumors., (© 2023. Controlled Release Society.)

Toxoplasma gondii is an obligate intracellular parasite in the phylum Apicomplexa that causes toxoplasmosis in humans and animals worldwide. Despite its prevalence, there is currently no effective vaccine or treatment for chronic infection. Although there are therapies against the acute stage, prolonged use is toxic and poorly tolerated. This study aims to explore the potential of repurposing topotecan and 10-hydroxycamptothecin (HCPT) as drugs producing double strand breaks (DSBs) in T. gondii. DSBs are mainly repaired by Homologous Recombination Repair (HRR) and Non-Homologous End Joining (NHEJ). Two T. gondii strains, RHΔHXGPRT and RHΔKU80, were used to compare the drug's effects on parasites. RHΔHXGPRT parasites may use both HRR and NHEJ pathways but RHΔKU80 lacks the KU80 protein needed for NHEJ, leaving only the HRR pathway. Here we demonstrate that topotecan and HCPT, both topoisomerase I venoms, affected parasite replication in a concentration-dependent manner. Moreover, variations in fluorescence intensity measurements for the H2A.X phosphorylation mark (γH2A.X), an indicator of DNA damage, were observed in intracellular parasites under drug treatment conditions. Interestingly, intracellular replicative parasites without drug treatment show a strong positive staining for γH2A.X, suggesting inherent DNA damage. Extracellular (non-replicating) parasites did not exhibit γH2A.X staining, indicating that the basal level of DNA damage is likely to be associated with replicative stress. A high rate of DNA replication stress possibly prompted the evolution of an efficient repair machinery in the parasite, making it an attractive target. Our findings show that topoisomerase 1 venoms are effective antiparasitics blocking T. gondii replication., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest. There is no financial or non-financial assistance provided by a third party for the reported work. There is no financial interest or relationship related to the subject matter., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We have previously shown that the Tdp1 inhibitor, enamine derivative of usnic acid, the agent OL9-116, enhances the antitumor activity of topotecan. In the present study, we developed and validated LC-MS/MS method for the quantification of OL9-116 in mouse whole blood and studied pharmacokinetics of the agent. The substance OL9-116 was shown to be stable in the whole blood in vitro. Sample preparation included two steps: mixing 10 µL of a blood sample with 10 µL of 0.2 M ZnSO 4 aqueous solution, followed by protein precipitation with 100 µL of acetonitrile containing internal standard. Quantification of the compound was performed using SCIEX 6500 QTRAP mass spectrometer in MRM mode following chromatographic separation on a C8 reversed-phase column. The method was validated in terms of selectivity, linearity, accuracy, precision, recovery, and stability of the prepared sample. When the agent OL9-116 was administered intragastrically at a dose of 150 mg/kg, the maximum concentration in the blood (about 5000 ng/mL) was reached after 2-4 h followed by the distribution and elimination of the compound. A study of the antitumor activity of a combination of OL9-116 and topotecan against Lewis lung carcinoma revealed that administration of topotecan 3 h after OL9-116 resulted in the most pronounced antitumor effect compared to simultaneous or individual administration of both compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This review article focuses on the research progress made in the structural modifications of camptothecin (CPT), a potent cytotoxic natural alkaloid. CPT possesses a unique 5-fused ring structure and exhibits various beneficial activities such as anti-proliferative, anti-fungal, insecticidal, and anti-SARS-CoV-2 properties. CPT and its analogs, including Topotecan and Irinotecan, have been successfully developed and marketed as topoisomerase I inhibitors. To enhance the therapeutic potential of CPT, researchers have undertaken structural modifications primarily on the A, B, and E rings of the CPT core structure. These modifications aim to improve the efficacy, selectivity, and pharmacokinetic properties of CPT derivatives. The article reviews the advancements in hybridizing CPT with other bioactive compounds, the synthesis of novel CPT analogs, and their associated biological activities. Moreover, the structure-activity relationship (SAR) of these modified CPT derivatives is summarized to gain insights into their structure-function correlations. In addition to discussing the modifications and biological activities of CPT derivatives, the article also touches upon the mechanism of parent drug release. Many CPT derivatives are prodrugs, meaning they require metabolic activation to generate the active form of the drug. It is a resource for researchers interested in developing novel anti-tumor agents based on CPT, addressing the limitations associated with the parent drug, and exploring various aspects of CPT modifications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The prognosis of relapsed/refractory (R/R) neuroblastoma (NB) is dismal, calling for new therapeutic strategies. Venetoclax (VEN) is a highly selective, potent, orally bioavailable, BCL-2 inhibitor small-molecule that showed a synergistic effect with cyclophosphamide and topotecan (Cy-Topo) in murine NB models. Our aim was to evaluate the feasibility of VEN plus Cy-Topo in children with R/R NB. Four patients, who had previously failed > 3 lines of treatment, were treated with VEN plus Cy-Topo based on a 28-day schedule in an outpatient setting. BCL-2 expression in immunochemistry on tumor samples at relapse and the BCL2 gene status was evaluated in all patients. The main toxicity was hematological, with grade 4 neutropenia and thrombocytopenia occurring in all courses and leading to transient VEN discontinuation. Grade 3 oral mucositis was observed in 1/8 courses. No other grade 2-4 toxicities were observed. BCL-2 was expressed in all tumors, while no molecular abnormalities in the BCL-2 genes were detected. A stable disease was observed in all patients, without any progression during the study period. VEN plus Cy-Topo is well tolerated, with encouraging results that may be improved by testing the schedule in less advanced patients., (© 2023. The Author(s).)

Background: Topotecan, an antitumor drug with systemic exposure (SE)-dependent activity against many pediatric tumors has wide interpatient pharmacokinetic variability, making it challenging to attain the desired topotecan SE. The study objectives were to update our topotecan population pharmacokinetic model, to evaluate the feasibility of determining individual topotecan clearance using a single blood sample, and to apply this approach to topotecan data from a neuroblastoma trial to explore exposure-response relationships., Procedure: Our previous population pharmacokinetic and covariate model was updated using data from 13 clinical pediatric studies. A simulation-based Bayesian analysis was performed to determine if a single blood sample could be sufficient to estimate individual topotecan clearance. Following the Bayesian approach, single pharmacokinetic samples collected from a Children's Oncology Group Phase III clinical trial (ANBL0532; NCT0056767) were analyzed to estimate individual topotecan SE. Associations between topotecan SE and toxicity or early response were then evaluated., Results: The updated population model included the impact of patient body surface area (BSA), age, and renal function on topotecan clearance. The Bayesian analysis with the updated model and single plasma samples showed that individual topotecan clearance values were estimated with good precision (mean absolute prediction error ≤16.2%) and low bias (mean prediction error ≤7.2%). Using the same approach, topotecan SE was derived in patients from ANBL0532. The exposure-response analysis showed an increased early response after concomitant cyclophosphamide and topotecan up to a topotecan SE of 45 h ng/mL., Conclusions: A simple single-sample approach during topotecan therapy could guide dosing for patients, resulting in more patients reaching target attainment., (© 2023 Wiley Periodicals LLC.)

Purpose: We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131 I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL)., Methods: Patients received 131 I-mIBG on day 1, with intravenous topotecan daily on days 1-5. A second activity of 131 I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21-25. Peripheral blood stem cells were infused on day 31., Results: Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years)., Conclusion: MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

The increase in cancer diagnoses and cancer deaths, severe side effects of existing treatments and resistance to traditional treatments have generated a need for new anticancer treatments. Glioblastoma multiforme (GBM) is the most common, malignant and aggressive brain cancer. Despite many innovations regarding GBM treatment, the final outcome is still very poor, making it necessary to develop new therapeutic approaches. Cold atmospheric plasma (CAP) as well as plasma-activated liquids (PAL) are being studied as new possible approaches against cancer. The anticancer activity of PAL such as "plasma-activated water" (PAW) is dependent on the reactive chemical compounds present in the solution. Possible combinatory effects with conventional therapies, such as chemotherapeutics, may expand the potential of PAL for cancer treatment. We aim to explore the therapeutic properties of a combination of PAW and topotecan (TPT), an antineoplastic agent with major cytotoxic effects during the S phase of the cell cycle, on a GBM cancer cell line (U-251mg). Combined treatments with PAW and TPT showed a reduction in the metabolic activity and cell mass, an increase in apoptotic cell death and a reduction in the long-term survival. Single applications of PAW+TPT treatments showed a cytotoxic effect in the short term and an antiproliferative effect in the long term, warranting future exploration of combining PAW with chemotherapeutic agents as new therapeutic approaches.

Background: Yolk sac tumors (YST) are commonly encountered gonadal germ cell tumors in children, especially in the prepubertal age group. In addition to gonadal primary, it can occur in multiple extragonadal sites, of which sacrococcygeal, retroperitoneum, gastric and mediastinum are the commonest. There are 4 previous reports of primary penile YST., Case Report: We describe a primary penile yolk sac tumor in a child with achondroplasia., Conclusion: Yolk sac tumor can occur in the penis during the prepubertal period. Penile yolk sac tumor associated with achondroplasia has not been previously reported, but this could be incidental.

Purpose: Surgery, multiagent systemic chemotherapy, and radiation are used for patients with orbital retinoblastoma but are associated with unacceptable short- and long-term toxicity (including death). We studied orbital and systemic exposure of topotecan in the swine model after ophthalmic artery chemosurgery (OAC) and intravenous (IV) delivery., Methods: Landrace pigs (n = 3) underwent 30-minute OAC of topotecan (4 mg), and samples were serially obtained from the femoral artery and from a microdialysis probe inserted into the lateral rectus muscle sheath of the infused eye as a surrogate of the orbital irrigation. Animals were recovered, and, after a wash-out period, plasma and microdialysate samples from the contralateral eye were collected after a 30-minute IV infusion of topotecan (4 mg). Samples were quantified by high-performance liquid chromatography, and population pharmacokinetic analysis was conducted using MonolixSuite., Results: After OAC, median topotecan exposure in the orbit was 5624 ng × h/mL (range 3922-12531) compared to 23 ng × h/mL (range 18-75) after IV infusion. Thus, topotecan exposure in the orbit was 218-fold (range 75-540) higher after OAC than after IV infusion despite comparable systemic exposure (AUCpl) between routes (AUCpl, OAC: 141 ng × h/mL [127-191] versus AUCpl, IV: 139 ng × h/mL [126-186]). OAC was more selective to target the orbit because the median (range) orbital-to-plasma exposure ratio was 44 (28-65) after OAC compared to 0.18 (0.13-0.40) after IV infusion., Conclusions: OAC of topotecan resulted in higher orbital exposure than after IV infusion and was a more selective route for local drug delivery. Patients with orbital retinoblastoma may benefit from a multimodal treatment strategy including OAC therapy.

Aims: Ulcerative colitis is characterized as a chronic immune-mediated inflammatory condition, affecting the intestinal gastroenteric tissue. Previous studies revealed that Th-17 cells are key players in the pathogenesis of ulcerative colitis. RORγT (Retinoic-acid-receptor-related orphan receptor-gamma T) is a lineage-specific transcription factor of Th-17 cells and thus has a role in their differentiation. Transient inhibition of RORγT has been reported to attenuate the differentiation of Th-17 cells and secretion of interleukin-17 (IL-17). Here, we investigated the efficacy of topotecan in ameliorating ulcerative colitis in rodents, via inhibition of the RORγT transcription factor., Main Methods and Key Findings: Experimental ulcerative colitis was induced in rats by intrarectal acetic acid administration. Topotecan attenuated the severity of ulcerative colitis in rats by revoking neutrophils and macrophage infiltration to the colon. It also alleviated diarrhea and rectal bleeding and improved body weight. Further, attenuation of RORγT and IL-17 expression was observed in topotecan treated animals. Levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β in the colon tissue were reduced by topotecan treatment. Significant reduction in malondialdehyde level, elevation of superoxide dismutase (SOD) and catalase activity was observed in the colon tissue of rats treated with topotecan compared to the diseased group., Significance: This study shows the therapeutic potential of topotecan in attenuating ulcerative colitis in rats probably via inhibition of the RORγT transcription factor and downstream mediators of Th-17 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but the contribution of non-CRL targets is unknown. Here, CRISPR screens map MLN4924-monotherapy sensitivity in retinoblastoma to a classic DNA damage-induced p53/E2F3/BAX-dependent death effector network, which synergizes with Nutlin3a or Navitoclax. In monotherapy-resistant cells, MLN4924 plus standard-of-care topotecan overcomes resistance, but reduces DNA damage, instead harnessing ribosomal protein nucleolar-expulsion to engage an RPL11/p21/MYCN/E2F3/p53/BAX synergy network that exhibits extensive cross-regulation. Strikingly, unneddylatable RPL11 substitutes for MLN4924 to perturb nucleolar function and enhance topotecan efficacy. Orthotopic tumors exhibit complete responses while preserving visual function. Moreover, MLN4924 plus melphalan deploy this DNA damage-independent strategy to synergistically kill multiple myeloma cells. Thus, MLN4924 synergizes with standard-of-care drugs to unlock a nucleolar death effector network across cancer types implying broad therapeutic relevance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC)., Methods: Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m 2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT01600573., Results: Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3-4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0-5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment., Conclusion: The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit., (© 2023. The Author(s).)

Background: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors., Methods: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m 2 /dose, with a de-escalation DL of 100 mg/m 2 /dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1., Results: The median age of 14 eligible patients was 11.5 years (range: 1-23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose-limiting toxicity (DLT)-evaluable patients received a median of four cycles (range: 1-6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL-6) concentrations (N = 6) showed sustained IL-6 reductions with decrease to normal values by day 21 in all patients, indicating potential on-target effects., Conclusions: The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m 2 /dose., (© 2023 Wiley Periodicals LLC.)

Background: Access to intra-arterial chemotherapy for retinoblastoma in low- and middle-income countries (LMICs) is limited. There is a need to optimize the efficacy of systemic chemotherapy for advanced intraocular retinoblastoma, particularly in LMICs. The aim was to compare the efficacy of standard versus higher dose carboplatin-based intravenous chemotherapy for group D and E retinoblastoma., Methods: The single-center, single-blinded, randomized study was conducted during 2019-2021. Patients with newly diagnosed group D or E retinoblastoma were randomized to receive vincristine, etoposide, and standard versus higher dose (<36 months: 18.6 vs. 28 mg/kg; ≥36 months: 560 vs. 840 mg/m 2 ) carboplatin. Examination under anesthesia and ultrasonography was performed at diagnosis and following three cycles of chemotherapy. Group E eyes with poor likelihood of globe/vision salvage at diagnosis were excluded., Results: Thirty-two eyes of 30 patients were analyzed: 17 group D and 15 group E eyes. The tumor response to chemotherapy with regards to regression pattern (p = .72), tumor shrinkage (diameter: p = .11, height: p = .96), subretinal seeds (p = .91), and vitreous seeds (p = .9) were comparable between the two treatment arms. The globe salvage (group D [82% vs. 67%; p = .58]; group E [12.5% vs. 29%; p = .57]) and salvage of meaningful vision (group D [100% vs. 75%; p = .13]; group E [100% vs. 50%; p = .48]) were comparable between standard and higher dose arms. No excess treatment-related toxicity was observed in the higher dose arm., Conclusions: Higher dose carboplatin-based intravenous chemotherapy did not result in superior globe or vision salvage in group D or E retinoblastoma., (© 2023 Wiley Periodicals LLC.)

Background: This was an open-label, multicenter, single-arm phase Ib dose-escalation study of oral LCL161 administered in combination with oral topotecan in patients with relapsed/refractory small cell lung cancer (SCLC) and select gynecological cancers., Methods: Cohorts of 3-6 patients initiated treatment with LCL161 and topotecan in escalating doses. LCL161 was administered orally on days 1, 8, and 15 of each 21-day cycle; topotecan was administered orally for the first 5 days of each 21-day cycle., Results: A total of 35 patients were enrolled in 6 cohorts; 30 patients were female; 4 patients had SCLC and 19 patients had ovarian cancer. Median prior lines of therapy were 3 (1-10). Median duration of treatment was 7.1 weeks (0.1-174). The most frequent grade 3/4 treatment-related adverse events were thrombocytopenia (51.43%) and anemia (31.43%). ORR was 9.7%; 58% of patients had SD. The study was stopped early before the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) were determined., Conclusion: The addition of LCL161 to oral topotecan caused more myelosuppression when dosed together than what was associated with either drug alone. Moreover, the drug combination did not improve outcomes. The study was terminated early (ClinicalTrials.gov Identifier: NCT02649673)., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance., Methods: Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018) were retrospectively analyzed., Results: Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively., Conclusion: Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

1-(Dimethylamino)methyl-6-quinolinol scaffold, a structural moiety of the molecule of anticancer drug topotecan, was modified into copper-containing products to study cytotoxic properties. New mononuclear and binuclear Cu(II) complexes with 1-(N,N-dimethylamino)methyl-6-quinolinol were synthesized for the first time. The same way Cu(II) complexes with 1-(dimethylamino)methyl-2-naphtol ligand were synthesized. The structures of mono- and binuclear Cu(II) complexes with 1-aminomethyl-2-naphtol were confirmed by X-ray diffraction. The obtained compounds were examined for in vitro cytotoxic activity against Jurkat, K562, U937, MDA-MB-231, MCF7, T47D, and HEK293 cells. The induction of apoptosis and the effect of novel Cu complexes on the cell cycle were investigated. The cells showed a higher sensitivity to mononuclear Cu(II) complex with 1-(N,N-dimethylamino)methyl-6-quinolinolligand. All synthesized Cu(II) complexes had higher antitumor activity than the drugs topotecan, camptothecin, and platinum containing cisplatin., (© The Author(s) 2023. Published by Oxford University Press.)

Herein, a series of 11- or 12-substituted benzophenanthridinone derivatives was designed and synthesized for the discovery of dual topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme-based assays indicated that two compounds 12 and 38 showed high TOP1 inhibitory potency (+++), and four compounds 35, 37, 39 and 43 showed good TDP1 inhibition with IC 50 values ranging from 10 to 18 μM. 38 could induce cellular TOP1cc formation, resulting in the highest cytotoxicity against HCT-116 cells (0.25 μM). The most potent TDP1 inhibitor 43 (10 μM) could induce cellular TDP1cc formation and enhance topotecan-induced DNA damage and showed strong synergistic cytotoxicity with topotecan in both MCF-7 and MCF-7/TDP1 cells., (© 2023 Wiley-VCH GmbH.)

Local chemotherapy using polymer drug delivery systems has the potential to treat some cancers, including intraocular retinoblastoma, which is difficult to treat with systemically delivered drugs. Well-designed carriers can provide the required drug concentration at the target site over a prolonged time, reduce the overall drug dose needed, and suppress severe side effects. Herein, nanofibrous carriers of the anticancer agent topotecan (TPT) with a multilayered structure composed of a TPT-loaded inner layer of poly(vinyl alcohol) (PVA) and outer covering layers of polyurethane (PUR) are proposed. Scanning electron microscopy showed homogeneous incorporation of TPT into the PVA nanofibers. HPLC-FLD proved the good loading efficiency of TPT (≥85%) with a content of the pharmacologically active lactone TPT of more than 97%. In vitro release experiments demonstrated that the PUR cover layers effectively reduced the initial burst release of hydrophilic TPT. In a 3-round experiment with human retinoblastoma cells (Y-79), TPT showed prolonged release from the sandwich-structured nanofibers compared with that from a PVA monolayer, with significantly enhanced cytotoxic effects as a result of an increase in the PUR layer thickness. The presented PUR-PVA/TPT-PUR nanofibers appear to be promising carriers of active TPT lactone that could be useful for local cancer therapy.

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: Compare lurbinectedin versus other second-line (2L) small-cell lung cancer (SCLC) treatments. Methods: An unanchored matching-adjusted indirect comparison connected the platinum-sensitive SCLC cohort of a single-arm lurbinectedin trial to a network of three randomized controlled trials (oral and intravenous [IV] topotecan, and platinum re-challenge) identified by systematic literature review. Network meta-analysis methods estimated relative treatment effects. Results: In platinum-sensitive patients, lurbinectedin demonstrated a survival benefit and favorable safety profile versus oral and IV topotecan and platinum re-challenge (overall survival, hazard ratio [HR]: 0.43; 95% credible interval [CrI]: 0.27, 0.67; HR: 0.43; 95% CrI: 0.26, 0.70; HR: 0.42; 95% CrI: 0.30, 0.58 respectively). Conclusion: Lurbinectedin showed a robust survival benefit and favorable safety versus other SCLC treatments in 2L platinum-sensitive SCLC.

Background: Recurrent high-grade neuroendocrine cervical cancer has a very poor prognosis and limited active treatment options., Objective: This study aimed to evaluate the efficacy of the 3-drug regimen of topotecan, paclitaxel, and bevacizumab in women with recurrent high-grade neuroendocrine cervical cancer., Study Design: This retrospective cohort study used data from the Neuroendocrine Cervical Tumor Registry (NeCTuR), which include data abstracted directly from medical records of women diagnosed with high-grade neuroendocrine carcinoma of the cervix from English- and Spanish-speaking countries. The study compared women with recurrent high-grade neuroendocrine cervical cancer who received the topotecan, paclitaxel, and bevacizumab regimen as first- or second-line therapy for recurrence and women with recurrent high-grade neuroendocrine cervical cancer who received chemotherapy but not the topotecan, paclitaxel, and bevacizumab regimen. Patients continued chemotherapy until disease progression or the development of unacceptable toxic effects. Progression-free survival from the start of therapy for recurrence to the next recurrence or death, overall survival from the first recurrence, and response rates were evaluated., Results: The study included 62 patients who received the topotecan, paclitaxel, and bevacizumab regimen as first- or second-line therapy for recurrence and 56 patients who received chemotherapy but not the topotecan, paclitaxel, and bevacizumab regimen for recurrence. The median progression-free survival rates were 8.7 months in the topotecan, paclitaxel, and bevacizumab regimen group and 3.7 months in the non-topotecan, paclitaxel, and bevacizumab regimen group, with a hazard ratio for disease progression of 0.27 (95% confidence interval, 0.17-0.48; P<.0001). In the topotecan, paclitaxel, and bevacizumab regimen group, 15% of patients had stable disease, 39% of patients had a partial response, and 18% of patients had a complete response. Compared with patients in the non-topotecan, paclitaxel, and bevacizumab regimen group, significantly more patients in the topotecan, paclitaxel, and bevacizumab regimen group remained on treatment at 6 months (31% vs 67%, respectively; P=.0004) and 1 year (9% vs 24%, respectively; P=.02). The median overall survival rates were 16.8 months in the topotecan, paclitaxel, and bevacizumab regimen group and 14.0 months in the non-topotecan, paclitaxel, and bevacizumab regimen group, with a hazard ratio for death of 0.87 (95% confidence interval, 0.55-1.37)., Conclusion: Combination therapy with topotecan, paclitaxel, and bevacizumab was an active regimen in women with recurrent high-grade neuroendocrine cervical cancer and improved progression-free survival while decreasing the hazard ratio for disease progression., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy and toxicity of intravitreal carboplatin plus melphalan for the treatment of vitreous seeds in eyes with retinoblastoma (RB)., Methods: This retrospective series at a tertiary referral center included 22 consecutive RB patients who had received intravitreal carboplatin (16 μg per 0.05 ml) combined with melphalan (30 μg in 0.03 ml) [IVi (Ca-Me)] for treatment of vitreous seeds. Tumor control and drug toxicities were recorded., Results: There were 22 eyes of 22 patients, divided into primary group (n = 13) without history of previous intravitreal chemotherapy (IViC) and refractory group (n = 9) with history of previous IViC using melphalan and/or topotecan. The demographics and clinical findings of the primary and refractory groups did not differ significantly. The 6-month follow-up revealed complete vitreous seed control (77% vs. 89%, p = 0.47). Vitreous seed recurrence was detected in 1 eye of each group at 6 months. During the next 18-month follow-up period, no recurrence of seed was observed. The response to IVi (Ca-Me) was not significantly influenced by previous IViC (p = 0.70), primary systemic or intra-arterial chemotherapy (p = 0.45), or the type of regression (p = 0.35). The most common tumor treatment complications were retinal detachment (RD) (n = 2), early hypotony (n = 2) and late hypotony (n = 4, unrelated), cataract (n = 2), and severe pigment dispersion (n = 1). Enucleation was performed in 8 eyes, for total RD (n = 1), phthisis bulbi (n = 5), and extensive solid tumor recurrence (n = 2). There was no case of orbital invasion, systemic metastasis, or death., Conclusion: Based on this interventional case series for primary and refractory vitreous RB seeds, carboplatin plus melphalan therapy may be effective with few toxic side effects., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The objective of this study was to monitor and identify adverse events (AEs) associated with topotecan, a medication used for the treatment of solid tumors, in order to improve patient safety and guide medication usage., Methods: To assess the disproportionality of topotecan-related AEs in real-world data, four algorithms (ROR, PRR, BCPNN, and EBGM) were employed as measures to detect signals of topotecan-associated AEs., Results: A statistical analysis was conducted using data from the FAERS database, encompassing 9,511,161 case reports from 2004Q1 to 2021Q4. Among these reports, 1,896 were identified as primary suspected (PS) AEs related to topotecan, and 155 topotecan-related adverse drug reactions (ADRs) at the preferred terms (PTs) level were selected. The occurrence of topotecan-induced ADRs was analyzed across 23 organ systems. The analysis revealed several expected ADRs, such as anemia, nausea, and vomiting, which were consistent with the drug labels. Additionally, unexpected significant ADRs associated with eye disorders at the system organ class (SOC) level were identified, indicating potential adverse effects not currently mentioned in the drug instructions., Conclusion: This study identified new and unexpected signals of adverse drug reactions (ADRs) related to topotecan, providing valuable insights into the relationship between ADRs and topotecan usage. The findings highlight the importance of ongoing monitoring and surveillance to detect and manage AEs effectively, ultimately improving patient safety during topotecan treatment.

Objective: To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma., Methods: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m 2 plus topotecan 0.75 mg/m 2 days 1-3 (n = 223) vs cisplatin 50 mg/m 2 plus paclitaxel 135 or 175 mg/m 2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS., Results: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones., Conclusions: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062., Competing Interests: Declaration of Competing Interest Dr. Tewari reports receiving honoraria for lectures, presentations, speakers' bureaus for Merck, Astra Zeneca, Eisai, Seagen, Tesaro and Clovis. He also reports serving on Data Safety Monitoring Board/Advisory Board for Iovance. Dr. Penson reports grants received from Array BioPharma Inc., AstraZeneca, Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis US LLC, Tesaro Inc. and Vascular Biogenics Ltd. Dr. Penson also reports receiving consulting fees from AstraZeneca, Eisai, GSK Inc., ImmunoGen Inc., Merck & Co, Mersana, Novacure, Roche Pharma, Sutro Biopharma, and Vascular Biogenics Ltd. and reports participating on Advisory Boards for AstraZeneca and Roche Pharma. Dr. Oaknin reports grants to her institution from the following: Abbvie Deutschland Gmbh & Co Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, AstraZeneca AB, BeiGene USA, Inc., Belgian Gynecological Oncology Group (BGOG), Bristol-Myers Squibb International Corporation (BMSM Clovis Oncology, Corcept Therapeutics, Eisai, F. Hoffmann-La Roche, Grupo Española de Investigación en Cáncer de Ovario (GEICO)), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Healthcare, Merck Sharp & Dohme, Millennium Pharmaceuticals, Unipharm Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem. Dr. Oaknin also reports receiving consulting fees from: Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs, and Sutro Biopharma, Inc., and GEICO. Dr. Oaknin reports personally receiving honoraria for lectures, presentations and Speakers bureaus from ESMO, Edizioni Minerva Medica SpA, Doctaforum Servicios S.L and received support for travel from Roche, AstraZeneca, PharmaMar as well as Clovis. Dr. Oaknin participated on Data Safety Monitoring Board/Advisory Board for Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, GOG, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs and Sutro Biopharma. Dr. Leitao reports receiving consulting fees from Medtronic, honoraria for lectures from Intuitive Surgical, Inc. as an Ad-hoc Speaker and participating on an Advisory Board for JnJ/Ethicon. Dr. Monk reports receiving consulting fees from the following: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, UmmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pleris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem and Zentalis. He also reports receiving honoraria from: AstraZeneca, Merck, Myriad, Tesaro/GSK, Roche/Genentech, Clovis and Easai. All other authors had no conflicts of interest to disclose with regard to this Study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study aims to develop an electroanalytical method to determine one of the most significant antineoplastic agents, topotecan (TPT), using a novel and selective molecular imprinted polymer (MIP) method for the first time. The MIP was synthesized using the electropolymerization method using TPT as a template molecule and pyrrole (Pyr) as the functional monomer on a metal-organic framework decorated with chitosan-stabilized gold nanoparticles (Au-CH@MOF-5). The materials' morphological and physical characteristics were characterized using various physical techniques. The analytical characteristics of the obtained sensors were examined by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV). After all characterizations and optimizing the experimental conditions, MIP-Au-CH@MOF-5 and NIP-Au-CH@MOF-5 were evaluated on the glassy carbon electrode (GCE). MIP-Au-CH@MOF-5/GCE indicated a wide linear response of 0.4-70.0 nM and a low detection limit (LOD) of 0.298 nM. The developed sensor also showed excellent recovery in human plasma and nasal samples with recoveries of 94.41-106.16 % and 95.1-107.0 %, respectively, confirming its potential for future on-site monitoring of TPT in real samples. This methodology offers a different approach to electroanalytical procedures using MIP methods. Moreover, the high sensitivity and selectivity of the developed sensor were illustrated by the ability to recognize TPT over potentially interfering agents. Hence, it can be speculated that the fabricated MIP-Au-CH@MOF-5/GCE may be utilized in a multitude of areas, including public health and food quality., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)