Cancer Chemotherapy and Pharmacology最新文献

Purpose: Cyclophosphamide is a widely used anticancer agent, though its clinical application is often constrained by myelotoxicity. Infliximab, a monoclonal antibody targeting TNF-α, may alleviate this toxicity by mitigating oxidative stress. This study aimed to assess the protective effects of infliximab against cyclophosphamide-induced myelotoxicity, focusing on bone marrow and spleen-related parameters.

Methods: Male Wistar rats (260 ± 20 g) were randomly divided into four groups (n = 5 each): Control (normal saline), Infliximab (7 mg/kg, IP), Cyclophosphamide (200 mg/kg, IP), and Infliximab + Cyclophosphamide (same respective doses with a four-day interval between administrations). Nine days after the initiation of the experiment, bone marrow and spleen histopathology, bone marrow cellularity, spleen index, and levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in bone marrow tissue, along with serum TNF-α and G-CSF concentrations, were evaluated.

Results: Infliximab prevented myelofibrosis in bone marrow tissue; however, it did not mitigate cellularity depletion. It failed to counteract the effects of cyclophosphamide on spleen histology and the spleen index. Additionally, infliximab enhanced antioxidant activity in the bone marrow. Moreover, inhibition of TNF-α was associated with an increase in G-CSF levels.

Conclusion: Although infliximab improved molecular pathways associated with cyclophosphamide-induced bone marrow and hematologic toxicity in the rat model, it did not lead to significant improvements in clinical manifestations.

Background: In glioblastoma, the heterogeneity of tumors often complicates treatment outcomes, particularly resistance to temozolomide (TMZ). This study aimed to investigate the expression characteristics of MCM10 in gliomas and its potential role in TMZ resistance.

Methods: Analyze the expression of MCM10 in glioma cells within the datasets Glioma_GSE102130, Glioma_GSE130224, Glioma_GSE131928_10X, and Glioma_GSE131928_Smartseq2 using the TISCH2 single-cell database.Subsequently, the expression level of MCM10 was evaluated using the TMZ-resistant cell lines U251-TR and LN229-TR. Glioma cells with reduced MCM10 expression were constructed through lentiviral interference.Construct glioma cells with MCM10 knockdown through lentiviral interference. Additionally, this study conducts an association analysis between MCM10 expression and patterns of DNA methylation and RNA methylation.Finally, the function of MCM10 was validated in a heterotopic mouse model.

Results: MCM10 mRNA is highly expressed in osteoclast-like malignant cells (OC-likemalignant cells) and oligodendrocyte progenitor-like malignant cells (OPC-like malignant cells). After treatment with TMZ, the levels of MCM10 protein and mRNA significantly increased. Knocking down MCM10 significantly reduced the migration and invasion of U251 and LN229 cells, while altering the expression of molecular markers associated with epithelial-mesenchymal transition (EMT). Weighted gene co-expression network analysis (WGCNA) revealed signaling pathways associated with drug resistance and identified overlapping differentially expressed mRNAs between resistant cells and MCM10 knockdown cells. High expression of MCM10 is associated with low DNA methylation, and MCM10 methylation is positively correlated with patient survival rates. Furthermore, inhibition of MCM10 significantly slowed tumor growth, indicating its potential as a therapeutic target for gliomas.

Conclusion: MCM 10 is a key mediator of TMZ resistance in glioblastoma.

Purpose: It has been reported that treatment response does not necessarily correlate with the change of thyroglobulin (Tg) during dabrafenib treatment in differentiated thyroid carcinoma (DTC). This study aimed to assess the association between the clinical response and Tg changes or inflammatory biomarkers in a real-world setting.

Methods: This retrospective multi center cohort study included 22 BRAF-mutated DTC patients treated with dabrafenib plus trametinib in three academic institutions.

Results: All 22 patients harbored the BRAFV600E mutation. Twenty-one patients (95%) had papillary thyroid carcinoma histology, and one had poorly differentiated thyroid carcinoma histology. Among 16 patients without Tg antibody, 14 patients (88%) experienced an increase in their Tg levels one month after the initiation of dabrafenib plus trametinib. In addition, 11 patients (69%) experienced an increase in their Tg levels at the best clinical response. Among these 11 patients who had an increase in Tg level at the best clinical response, the numbers of patients who had partial response, stable disease, and progressive disease were 3, 8, and 0, respectively. Among the 19 patients in whom neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio were measured at baseline, no distinctive trends were identified between clinical response and change in those inflammatory biomarkers.

Conclusions: Tg changes during dabrafenib plus trametinib treatment may not be associated with clinical response to dabrafenib plus trametinib treatment. Further study is needed to clarify the association between Tg level or inflammatory biomarkers change and clinical response to dabrafenib plus trametinib treatment.

Purpose: This systematic review investigates drug repurposing as a strategy to accelerate and improve cancer treatment by specifically examining how existing medications can effectively target the established hallmarks of cancer. The research explores how repurposed drugs can address the challenges of conventional cancer drug development, including high costs, lengthy development timelines, and frequent clinical failures.

Methods: The review systematically analyzes repurposed drugs with their ability to target specific cancer hallmarks, including oncogenic signaling pathways, cell death regulation, metabolic reprogramming, growth suppressor reactivation, phenotypic plasticity, antitumor immunity, telomerase activity, angiogenesis, inflammation, cellular senescence, invasion and metastasis, DNA damage response, microbiome modulation, and epigenetic regulation.

Results: The analysis identified several promising repurposed medications targeting specific cancer hallmarks: artemisinin derivatives for oncogenic signalling, niclosamide for cell death pathways, leflunomide for metabolic dysregulation, statins for tumour suppressor reactivation, metformin for phenotypic plasticity, liothyronine for immune activation, PARP inhibitors for replication, itraconazole for angiogenesis, celecoxib for inflammation, BCL-2 inhibitors for senescence, fluoroquinolones for metastasis, spironolactone for DNA damage, isoliquiritigenin for microbiome modulation, and various agents targeting non-mutational epigenetic regulation.

Conclusion: Drug repurposing represents an intriguing approach for addressing the limitations of traditional cancer drug development while effectively targeting the fundamental hallmarks of cancer. By leveraging existing medications with established safety profiles, this strategy offers potential for more rapid translation to clinical applications and may enhance the therapeutic arsenal against various cancer types.

Purpose: Carboplatin is a widely used antineoplastic drug, but it is associated with severe adverse effects, including peripheral neuropathy. However, the neurobiological mechanisms underlying this side effect are not fully known. Thus, we determined neurochemical changes in the lumbar dorsal root ganglia (DRG) and spinal cord following carboplatin treatment.

Methods: Male BALB/c (23 weeks-old) mice received carboplatin (i.p.; 60 mg/kg/week for 4 weeks) or vehicle. Hindpaw mechanical sensitivity was evaluated at baseline and after carboplatin administration. On day 30 post-first carboplatin administration, mice were euthanized, and the lumbar spinal cord and DRG were processed for immunohistochemistry. Within the L4 DRG, we determined the percentage of neurons expressing the neuropeptide CGRP and the cell injury marker ATF3. Macrophage (CD68, CD163), and blood vessel density (endomucin) were also determined in the DRG. In the spinal cord, we examined the expression of several neuropeptides (CGRP, galanin, NPY) and a marker for astrocyte activation (GFAP).

Results: Carboplatin-treated mice displayed hindpaw mechanical hypersensitivity. The percentage of DRG neurons expressing CGRP and ATF3 as well as the density of CD68⁺ macrophages were significantly greater in carboplatin- compared to vehicle-treated mice. Conversely, the density of CD163⁺ macrophages was significantly reduced in carboplatin- compared to vehicle-treated mice. In the spinal dorsal horn, carboplatin-treated mice showed significantly greater CGRP, galanin, and NPY expression than vehicle-treated mice. There were no changes in the density of endomucin⁺ blood vessels and GFAP immunoreactivity between groups in the DRG and spinal cord, respectively.

Conclusion: Carboplatin induced several neurochemical changes in the mouse DRG and spinal cord, which may contribute to the development of carboplatin-induced peripheral neuropathy.

Purpose: Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), is approved in combination with chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer (in Japan) and in combination with fluoropyrimidine- and platinum-containing chemotherapy for first-line locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (in geographies including but not limited to the US, Europe, and China). Noncompartmental analysis (NCA) was previously used to evaluate the effect of zolbetuximab on pharmacokinetics (PK) of 5-fluorouracil (5-FU) and oxaliplatin; however, limitations of NCA confounded the results. This study utilized population pharmacokinetic (PopPK) analysis to address these limitations.

Methods: In Cohort 2 of the phase 2 ILUSTRO study (NCT03505320), patients with locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive G/GEJ adenocarcinoma received zolbetuximab with modified folinic acid, 5-FU, and oxaliplatin. PopPK models were developed to evaluate the impact of zolbetuximab on PK of 5-FU and oxaliplatin (including simultaneous analysis of free and total platinum).

Results: PK of 5-FU was adequately described by a 1-compartment model with zero-order input and first-order elimination. PK of free and total platinum was simultaneously described by a 3-compartment model with zero-order input, first-order elimination, and time-dependent free fraction. No impact of zolbetuximab on 5-FU PK or on systemic clearance or free fraction of oxaliplatin in plasma was observed. The effect of zolbetuximab on oxaliplatin distribution volume (12.3% decrease) was statistically significant but not considered clinically relevant.

Conclusion: PopPK analysis suggests no effect of zolbetuximab on 5-FU or oxaliplatin PK.

Purpose: Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, is used to treat lymphoplasmacytic lymphoma (LPL). A hallmark complication of LPL is hyperviscosity syndrome (HVS), caused by markedly elevated serum IgM levels. Plasma exchange (PE) is a standard treatment for HVS but may also remove circulating drugs, particularly those with high protein binding, potentially reducing drug exposure and efficacy. Evaluating the impact of PE on the pharmacokinetics of drugs used to treat LPL is important for optimal treatment.

Methods: We report the case of a 63-year-old man with LPL who presented with acute headache and was diagnosed with HVS. Tirabrutinib (480 mg, once daily) was initiated, and PE was performed the next day because of persistent IgM elevation. To assess the impact of PE on tirabrutinib plasma concentrations, blood samples were collected approximately 3 h prior to PE (C15), immediately before PE (C18), and immediately after PE (C20).

Results: The concentrations at C15, C18 and C20 were 33.3, 16.9, and 11.4 ng/mL, respectively. The elimination rate constant (ke) was calculated as 0.226 h⁻¹ before PE and 0.197 h⁻¹ during PE. Based on the pre-PE ke, the predicted post-PE concentration (C20) assuming no PE was approximately 10.6 ng/mL, slightly lower than the observed value.

Conclusion: PE appeared to have minimal impact on the tirabrutinib plasma concentration, likely due to its large volume of distribution. Although further cases are needed, this case supports the feasibility of concomitant PE during tirabrutinib therapy without significant compromise of drug efficacy.

Purpose: The alternative splicing of mRNA precursors allows one gene to yield multiple proteins with distinct functions. CDC-like kinases serve as pivotal regulators of alternative splicing. Control of protein expression also occurs at the level of DNA through histone methylation and demethylation. We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents.

Methods: Well-characterized patient-derived cancer cell lines from the PDMR ( https://pdmr.cancer.gov/models/database.htm ) were used along with standard human cancer cell lines. Multi-cell type-tumor spheroids were grown from a ratio of 6:2.5:1.5 malignant cells, endothelial cells, and mesenchymal stem cells. Following three days of growth, the spheroids were exposed to the single agents or combinations at concentrations up to the clinical C_max value for each agent, if known. After seven days of exposure, cell viability was assessed using the CellTiter-Glo 3D assay and spheroid volume was assessed by bright field imaging.

Results: Several of the targeted oncology drugs exhibited additive and greater-than-additive cytotoxicity when combined with a CLK inhibitor, or the LSD1 inhibitor. These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors.

Conclusion: These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem.