Search Results (44)

Background: Pirtobrutinib has recently emerged as a promising first-line treatment option for chronic lymphocytic leukemia (CLL). Unlike currently established regimens, which are generally based on doublet combinations, pirtobrutinib can be administered as monotherapy. No head-to-head trials comparing pirtobrutinib with contemporary first-line combinations are currently available; hence, indirect comparative evidence may help define its potential role. Methods: A non-anchored indirect comparison based on reconstructed individual patient data (IPD) was conducted using published Kaplan–Meier curves from randomized controlled trials evaluating first-line treatments for CLL. Progression-free survival (PFS) was the endpoint of interest. Reconstructed IPD were generated using WebPlotDigitizer and the IPDfromKM algorithm. Then, Kaplan–Meier curves were plotted based on these patients, and the values of the restricted mean survival time (RMST) at 36 months were determined. Regarding PFS, pirtobrutinib monotherapy was compared indirectly with acalabrutinib plus obinutuzumab, venetoclax plus obinutuzumab, and venetoclax plus ibrutinib. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using univariate Cox models. The non-inferiority of pirtobrutinib monotherapy versus doublet regimens was assessed according to a non-inferiority margin set at HR = 1.15. Finally, the value-based prices of the new treatments were estimated based on a willingness-to-pay threshold of euro 30,000 per disease-free year gained and compared with the corresponding real prices in the Italian market. Results: The analysis included four randomized trials. Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696–1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066–1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684–3.1240) versus acalabrutinib plus obinutuzumab. Pirtobrutinib met the non-inferiority criterion compared with venetoclax plus obinutuzumab and venetoclax plus ibrutinib, but not with acalabrutinib plus obinutuzumab; however, these results were negatively affected by the small number of events in the pirtobrutinib arm, which generated wide CIs. In the preliminary pharmacoeconomic analysis, venetoclax plus obinutuzumab showed the most favorable profile in the comparison of value-based price vs. real price. Conclusions: This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL. Full article

Synchronous low-grade alimentary lymphoma and gastrointestinal mast cell tumor have recently been described in cats. This report describes synchronous low-grade alimentary lymphoma and gastrointestinal mast cell tumor involving the jejunum in a cat. A 2.3 kg, 15-year-old, spayed female Chinchilla Persian cat presented with vomiting, diarrhea, anorexia, and lethargy. Ultrasonography and computed tomography demonstrated diffuse intestinal wall thickening and a focal jejunal lesion characterized by marked transmural thickening with loss of wall layering. Exploratory laparotomy and full-thickness intestinal biopsies were conducted. Histopathologic and immunohistochemical examination revealed two morphologically distinct neoplastic populations involving different jejunal wall layers. The two populations were anatomically adjacent but remained distinct without convincing intermingling in the examined histologic sections. These findings supported the interpretation of a lesion most consistent with a collision pattern. The affected intestinal segment was surgically resected, and chlorambucil and prednisolone were administered postoperatively. Clinical signs resolved, imaging abnormalities improved, and no evidence of local gastrointestinal mast cell tumor recurrence or progression of low-grade alimentary lymphoma was detected during the 14-month follow-up period. This case expands the currently recognized morphologic spectrum of synchronous feline intestinal neoplasia and highlights the importance of comprehensive histopathologic assessment and full-thickness intestinal biopsies for accurate diagnosis. Full article

Chronic lymphocytic leukemia (CLL) is uncommon in Asia, and longitudinal genomic data from Asian cohorts are limited. We conducted serial whole-exome sequencing (WES) in a multicenter Korean cohort of newly diagnosed, elderly CLL treated with chlorambucil–obinutuzumab to evaluate mutational heterogeneity and clonal hematopoiesis of indeterminate potential (CHIP) during treatment and follow-up. Tumor-only variants were filtered, restricted to nonsynonymous or loss-of-function coding/splice-site mutations, and summarized as a binary patient-by-gene matrix for principal component analysis (PCA), trajectory analysis, and k-means clustering. CHIP was defined as ≥1 qualifying mutation in a prespecified CHIP gene set. Baseline PCA was more compact in patients with complete response at end of treatment, whereas partial response or progressive disease cases were more dispersed. PCA trajectories were compact and directionally consistent in complete responders, more dispersed in partial responders, and highly heterogeneous without a dominant direction in progressive disease. Clustering identified dispersed and compact clusters, and CHIP-associated mutations were enriched in the dispersed cluster (55.6% vs. 8.3%, Fisher’s exact p = 0.0086). In paired samples collected 3–5 months after end of treatment, CHIP status changed in some patients. Serial WES may provide complementary information to treatment response, although these observations require confirmation in larger cohorts. Full article

Background/Objectives: The aberrant epigenetic landscape of cancer cells has attracted wide attention, motivating the search for new epigenetically active drugs both for anticancer therapy and for overcoming the drug resistance promoted by epigenetic changes. The use of epi-drugs in cancer therapy requires consideration of the influence of applied treatment on epigenetic regulation of gene expression. Therefore, it is reasonable to screen epigenetically active compounds among the drugs widely used in clinical oncology. Methods: We applied the HeLa TI cell-based assay to analyze the epigenetic activity of 40 drugs including 22 chemotherapeutic, 2 immunotherapeutic, 13 targeted, and 3 palliative agents. Reactivation of the epigenetically silenced GFP reporter gene integrated into the genome of HeLa TI cells was assessed using flow cytometry. Results: Statistically significant increases in the proportions of GFP-positive cells were demonstrated for the alkylating agent chlorambucil; the antimetabolites cytarabine, fluorouracil, gemcitabine, and pemetrexed; the platinum-based compounds cisplatin, and oxaliplatin; the topoisomerase inhibitor topotecan; and the antimicrotubule agents docetaxel, vincristine, and eribulin. Epigenetic activity was also detected for the targeted-therapy agents AZD8055, wortmannin, and cetuximab, as well as for the corticosteroid dexamethasone. Thus, epigenetic activity was revealed for 15 drugs widely used in cancer therapy, which possess different modes of action. Conclusions: Our findings show that many anticancer therapy agents modulate the epigenetic landscape of cancer cells, providing a rationale for expanding their therapeutic applications and enhancing the efficacy of combination strategies by overcoming epigenetically driven chemoresistance. Full article

This paper reports the first case in which a hyperlipidemic retriever (due to hypothyroidism) with a nasal tumor was successfully treated—achieving partial remission—and managed using a metronomic combination of chlorambucil (3.74 mg/m², SID) and prednisolone (0.28 mg/kg, SID) orally for 9 months at a general practice. A 35 kg spayed female golden retriever aged 8 years and 8 months with nosebleeds visited the Bundang New York Animal Hospital in July 2023 after being diagnosed with nasal carcinoma. A protocol of 4 weeks of chemotherapy followed by 1 week of rest was repeated in two cycles and continued metronomically for 9 months without pause after the two cycles. The nasal exudate was significantly reduced. The size of the nasal tumor was monitored using computed tomography (CT) imaging at a referral hospital. Since the first occurrence of epistaxis, 18 months have passed (as of January 2025) and the nasal exudate is barely visible, and the vital signs and weight of the dog remain stable. The size of the nasal tumor significantly decreased after 9 months of chemotherapy completion without moderate side effects, and all the blood work was normalized, including hypercholesteremia. This study demonstrates that, in hyperlipidemic cancer patients, a prednisolone/chlorambucil metronomic combination which is cost-effective can be an alternative to tyrosine kinase inhibitors such as sorafenib, even when excluding the price. Through a literature review, the author also investigates the effect of the hyperlipidemic state on cancer, focusing on carcinoma and vascular endothelial growth factor (VEGF), as well as the RAS-RAF-MEK pathway, which is a target for tyrosine kinase inhibitors, in order to reveal the molecular mechanism of chlorambucil metronomic chemotherapy. Also, the author investigates the molecular pathway of carcinoma development in human hyperlipidemia patients through single-cell RNA sequence analysis using open public data, and discusses the molecular action of chlorambucil. Full article

Protein-losing nephropathy (PLN) involves a heterogeneous group of pathologies leading to selective glomerular damage and development of renal disease. ICGN, the main cause of PLN, requires immunosuppressive treatment. However, the scientific evidence in veterinary medicine on immunosuppressive therapeutic schemes in this condition is limited. The aim of this study is to describe the clinical and paraclinical evolution of five dogs with PLN, presumably associated with ICGN, treated with chlorambucil as immunosuppressive monotherapy. Suspected IGCN was established by the presence of a urine protein–creatinine ratio (UPC) ≥ 3 without response to standard therapy, hypoalbuminemia < 2, or progressive azotemia. Patients were treated with a dosage range of chlorambucil from 0.16 to 0.4 mg/kg (mean 0.25 mg/kg) every 24 h as the sole immunosuppressant. In the end, 4/5 patients showed significant clinical improvement, 3/3 had resolution of the nephrotic syndrome, 5/5 had a sustained decrease in UPC values during follow-up and no relevant adverse effects were observed. In this report, chlorambucil proved to be a well-tolerated and potentially effective monotherapy for immune-mediated PLN in dogs. Full article

Photolabile protecting groups (PPGs), also known as caging groups, are valuable tools in photopharmacology. They enable precise control over the release of bioactive compounds from the corresponding caged compounds at a precisely controlled time and place using light of specific wavelengths. This study introduces a novel approach to fine-tuning the photophysical and photochemical properties of visible-light-sensitive dicyanocoumarin- and COUPY-based caging groups by incorporating a phenyl group in a position adjacent to the photolabile bond. Our photoactivation studies with visible light demonstrated that this structural modification slightly improved the photolytic efficiency of both dicyanocoumarin- and COUPY-caged model compounds compared to their methyl-substituted or unsubstituted counterparts. Furthermore, COUPY PPGs were efficiently photoactivated with red light (620 nm) and successfully used to cage two antitumor drugs, chlorambucil and 4-phenylbutyric acid. These findings highlight the potential of phenyl-containing caging groups based on dicyanocoumarin and COUPY scaffolds as versatile platforms for developing new light-activated tools for photopharmacology applications. Full article

Background: This work presents a mechanistic nonlinear model, formulated as a system of first-order Ordinary Differential Equations, to investigate the dynamics of Chronic Lymphocytic Leukemia (CLL) under combined chemoimmunotherapy using CAR-T cells and chlorambucil. Methods: Leveraging nonlinear dynamical systems theory and a model-based design approach, we derive optimal dosing strategies through extensive in silico simulations, providing hemato-oncologists with actionable tools to refine CLL treatment. The model captures the short- and long-term impacts of both therapies on leukemia cell populations, enabling precise predictions of therapeutic outcomes. Results: By analyzing local and global system dynamics, we establish sufficient conditions for dosing and protocol design, offering a framework to optimize therapies based on individual patient responses. Comparisons of dose-escalation and -de-escalation strategies further demonstrate potential trajectories, such as complete eradication, partial response, or relapse, providing data-driven guidance for improving patient care. Conclusions: This study highlights the power of mathematical modeling in blood cancer research, enhancing the development of personalized and effective CLL treatment regimens. Full article

Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks. Full article

Chlorambucil is used in veterinary medicine for various cancers, while Toceranib, which was licenced for treating canine mast cell tumours, is now used against other solid tumours. Both drugs are generally safe, but their combined use has not been studied. This study aimed to investigate retrospectively the safety profile of the Chlorambucil–Toceranib combination against canine solid tumours. Thirty-eight dogs received this combination. Chlorambucil was administered at a median dose intensity of 15.1 mg/m² per week, while Toceranib was given at the median dosage of 2.5 mg/kg on a Monday–Wednesday–Friday schedule. Dosages were individually adjusted according to commercially available tablet formulation, co-morbidities, and adverse events (AEs). The resulting clinical benefit rate (CBR) and overall response rate (ORR) were 55.3% and 10.5%, respectively. The median progressive free survival (PFS) and median survival time (MST) were 45.5 (12–537) days and 259 (42–1178) days, respectively. Gastrointestinal AEs occurred in 39.5% of cases (n = 15), 15.8% (n = 6) experienced UPC elevation, while hematological and biochemistry AEs affected 13.2% (n = 5) each. Most of these AEs were grades 1–2 (G1–2). None of the dogs interrupted treatment due to AEs, and the combination appeared safe. Larger prospective clinical trials are required to confirm our findings and investigate its efficacy across various cancers. Full article

This study describes the synthesis and characterization of chlorambucil (CLB)-functionalized mesoporous silica nanoparticles (MSNs) for potential application in cancer therapy. The nanoparticles were designed with a diameter between 20 and 50 nm to optimize cellular uptake and avoid rapid clearance from the bloodstream. The synthesis method involved modifying a previously reported technique to reduce particle size. Successful functionalization with CLB was confirmed through various techniques, including Fourier transform infrared spectroscopy (FTIR) and elemental analysis. The cytotoxicity of the CLB-functionalized nanoparticles (MSN@NH₂-CLB) was evaluated against human lung adenocarcinoma cells (A549) and colon carcinoma cells (CT26WT). The results suggest significantly higher cytotoxicity of MSN@NH₂-CLB compared to unbound CLB, with improved selectivity towards cancer cells over normal cells. This suggests that MSN@NH₂-CLB holds promise as a drug delivery system for targeted cancer therapy. Full article

Chlorambucil-platinum(IV) prodrugs exhibit multi-mechanistic chemotherapeutic activity with promising anticancer potential. The platinum(II) precursors of the prodrugs have been previously found to induce changes in the microtubule cytoskeleton, specifically actin and tubulin of HT29 colon cells, while chlorambucil alkylates the DNA. These prodrugs demonstrate significant anticancer activity in 2D cell and 3D spheroid viability assays. A notable production of reactive oxygen species has been observed in HT29 cells 72 h post treatment with prodrugs of this type, while the mitochondrial membrane potential was substantially reduced. The cellular uptake of the chlorambucil-platinum(IV) prodrugs, assessed by ICP-MS, confirmed that active transport was the primary uptake mechanism, with platinum localisation identified primarily in the cytoskeletal fraction. Apoptosis and necrosis were observed at 72 h of treatment as demonstrated by Annexin V-FITC/PI assay using flow cytometry. Immunofluorescence measured via confocal microscopy showed significant changes in actin and tubulin intensity and in architecture. Western blot analysis of intrinsic and extrinsic pathway apoptotic markers, microtubule cytoskeleton markers, cell proliferation markers, as well as autophagy markers were studied post 72 h of treatment. The proteomic profile was also studied with a total of 1859 HT29 proteins quantified by mass spectroscopy, with several dysregulated proteins. Network analysis revealed dysregulation in transcription, MAPK markers, microtubule-associated proteins and mitochondrial transport dysfunction. This study confirms that chlorambucil-platinum(IV) prodrugs are candidates with promising anticancer potential that act as multi-mechanistic chemotherapeutics. Full article

Glucose transporters GLUT1 belong to the major facilitator superfamily and are essential to human glucose uptake. The overexpression of GLUT1 in tumor cells designates it as a pivotal target for glycoconjugate anticancer drugs. However, the interaction mechanism of glycoconjugate drugs with GLUT1 remains largely unknown. Here, we employed all-atom molecular dynamics simulations, coupled to steered and umbrella sampling techniques, to examine the thermodynamics governing the transport of glucose and two glycoconjugate drugs (i.e., 6-D-glucose-conjugated methane sulfonate and 6-D-glucose chlorambucil) by GLUT1. We characterized the specific interactions between GLUT1 and substrates at different transport stages, including substrate recognition, transport, and releasing, and identified the key residues involved in these procedures. Importantly, our results described, for the first time, the free energy profiles of GLUT1-transporting glycoconjugate drugs, and demonstrated that H160 and W388 served as important gates to regulate their transport via GLUT1. These findings provide novel atomic-scale insights for understanding the transport mechanism of GLUT1, facilitating the discovery and rational design of GLUT1-targeted anticancer drugs. Full article

Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that has been widely used for anti-tumor therapy by the generation of excessive highly cytotoxic ROS. However, the poor water solubility of the photosensitizer, reactive oxygen species (ROS) depleting by high concentrations of glutathione (GSH) in the tumor microenvironment and the activation of DNA repair pathways to combat the oxidative damage, will significantly limit the therapeutic effect of PDT. Herein, we developed a photosensitizer prodrug (CSP) by conjugating the photosensitizer pyropheophorbide a (PPa) and the DNA-damaging agent Chlorambucil (Cb) with a GSH-responsive disulfide linkage and demonstrated a multifunctional co-delivery nanoplatform (CSP/Ola nanoparticles (NPs)) together with DSPE-PEG₂₀₀₀ and PARP inhibitor Olaparib (Ola). The CSP/Ola NPs features excellent physiological stability, efficient loading capacity, much better cellular uptake behavior and photodynamic performance. Specifically, the nanoplatform could induce elevated intracellular ROS levels upon the in situ generation of ROS during PDT, and decrease ROS consumption by reducing intracellular GSH level. Moreover, the CSP/Ola NPs could amplify DNA damage by released Cb and inhibit the activation of Poly(ADP-ribose) polymerase (PARP), promote the upregulation of γ-H2AX, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. In vitro investigations revealed that CSP/Ola NPs showed excellent phototoxicity and the IC₅₀ values of CSP/Ola NPs against MDA-MB-231 breast cancer cells were as low as 0.05–01 μM after PDT. As a consequence, the co-delivery nanoplatform greatly promotes the tumor cell apoptosis and shows a high antitumor performance with combinational chemotherapy and PDT. Overall, this work provides a potential alternative to improve the therapeutic efficiency of triple negative breast cancer cell (TNBC) treatment by synergistically enhancing DNA damage and disrupting DNA damage repair. Full article

Increasing cases of cancer have been a primary concern in recent decades. Developing new chemotherapeutics is challenging and has been faced with limitations, such as multidrug resistance, poor specificity, selectivity, and toxicity. The aforementioned factors contribute to treatment failure. Hybrid compounds have features that can overcome the limitations mentioned above. Chlorambucil, an anticancer drug that is used to treat prostate and breast cancer, suffers from poor aqueous solubility and specificity, a short half-life, and severe side effects, including anaemia and bone marrow suppression. It compromises the immune system, resulting in treatment failure. Hence, its combination with other pharmacophores has been reported to result in effective anticancer agents with fewer side effects and high therapeutic outcomes. Furthermore, this review gives an update (2010 to date) on the developments of chlorambucil hybrid compounds with anticancer activity, and the structure-activity relationship (SAR), and also highlights future strategies for developing novel anticancer agents. Full article