The DNA methyltransferase (DNMT) inhibitor 4’-thio-2’-deoxycytidine (TdCyd), a second-generation cytidine analog, demonstrated potent preclinical antitumor activity and favorable pharmacokinetics, which led us to explore its safety, efficacy and anti-tumor activity in patients with solid tumors. Adult patients with advanced solid tumors received TdCyd orally on days 1–5 and 8–12 in 21-day cycles. Dose escalation proceeded according to design 4 of the Simon accelerated titration design, changing to a 3 + 3 dose escalation design in the event of dose-limiting toxicities. Blood samples were collected for circulating tumor cell (CTC) evaluation of p16 re-expression as a marker of TdCyd epigenetic modulation, and for pharmacokinetic analysis. Twenty-seven patients were enrolled. The maximum tolerated dose was not reached. The best response was prolonged stable disease (SD), with 3 patients on treatment for ≥ 6 cycles, and there was no dose-response relationship. An increase in the proportion of p16-expressing cytokeratin-positive (CK+) CTCs was detected in 71
Chimeric antigen receptor T cell (CAR-T) therapy has emerged as a prominent cancer treatment modality, demonstrating significant clinical success. To date, several CAR-T products have been approved by the U.S. Food and Drug Administration (FDA) for the management of hematological malignancies. Despite these advances, several challenges continue to limit the broader application of CAR-T therapy. These challenges include complex and costly manufacturing processes, safety concerns associated with integrating viral vectors, individualized production requirements, therapy-related adverse effects, and limited efficacy against solid tumors. Recent progress in ribonucleic acid (RNA)-based technologies has introduced promising strategies to improve the safety, adaptability, and therapeutic performance of CAR-T cells. This review provides a comprehensive translational perspective on the integration of RNA technologies with CAR-T therapy. Specifically, it categorizes current approaches into four key areas: RNA-driven non-viral CAR-T cell manufacturing, RNA vaccine-mediated enhancement of CAR-T activity, RNA interference (RNAi)-based modulation, and in vivo CAR-T cell generation. Among the reviewed approaches, ex vivo messenger RNA (mRNA)-based CAR-T engineering currently has the greatest clinical maturity, whereas RNA vaccine-mediated boosting shows particular promise for enhancing CAR-T expansion and persistence, especially in solid tumors. In vivo RNA-mediated CAR-T generation remains at an early stage of development, with evidence still predominantly derived from preclinical studies, but may ultimately represent the most transformative approach by simplifying manufacturing and improving accessibility. Trial registration number: Not applicable.
Our previous study identified compound 4a, a synthesized naphthoquinone–triazole hybrid, as as a promising cytotoxic agent. This study aimed to characterizes its pharmacokinetic parameters and absolute oral bioavailability in rats following single intravenous (IV) and oral administration. Male Sprague–Dawley rats received compound 4a via IV (1.5 mg/kg) or oral (5.0 mg/kg) administration. Plasma concentrations were quantified using a validated LC–MS/MS method. Pharmacokinetic parameters were calculated via non-compartmental analysis and compartmental modeling. Serum biomarkers were analyzed to assess acute renal and hepatic tolerability. The IV profile was best described by a three-compartment model, revealing a steady-state volume of distribution (Vss) of 496.80 mL/kg and an elimination half-life (t1/2) of 18 h. Oral administration resulted in rapid absorption but moderate bioavailability (13
Relapse following hematopoietic stem cell transplantation (HSCT) is a leading cause of transplant failure for pediatric acute leukemia patients, emphasizing the need for an effective post-transplant continuation therapy. This systematic review evaluates the role of tyrosine kinase inhibitors (TKIs) as a post-HSCT continuation therapy in pediatric acute leukemia. A literature search of PubMed, Cochrane, Web of Science, and VHL was conducted according to PRISMA guidelines. Original studies were included if they were relevant to the research question and fit the eligibility criteria. The initial search identified 765 articles, with 16 studies included after filtration. TKIs were indicated for patients with chromosomal alterations causing constitutively active kinase signaling. Common agents included imatinib, dasatinib, ponatinib, sorafenib, and gilteritinib, and selection was based on disease status and molecular profiling. Duration of continuation ranged from 10 months to 3 years, with dosage dependent on the agent and tolerability. TKIs were generally well-tolerated, with reported side effects including cytopenia, liver dysfunction, and skin conditions. Across the included studies, MRD negativity and sustained molecular remission were reported in selected patients receiving post-HSCT TKI continuation therapy, while relapse was also reported after treatment discontinuation or in resistant disease. However, optimal duration and long-term safety remain unclear in the pediatric population. TKIs can serve as a targeted post-HSCT continuation therapy in select pediatric acute leukemia patients, particularly those with high-risk, mutation-driven disease. Molecular profiling and MRD monitoring are central to guiding agent selection, timing, and mutation-directed therapy adjustments. These findings support individualized TKI treatment to reduce relapse risk following HSCT, while highlighting the need for prospective studies to define standardized treatment strategies. Post-HSCT TKI continuation can reduce relapse risk in pediatric acute leukemia. Agent selection is guided by disease status and molecular profiling. Ongoing MRD surveillance and individualized continuation strategies are necessary. Pediatric dosing and continuation duration remain undefined.
Intestinal toxicity is a major adverse effect of irinotecan (IRT) chemotherapy, and effective preventive treatments are lacking. This study evaluated the impact of IRT on (i) duodenal motility and mucosal barrier function, (ii) histopathological changes along the small intestine and colon, and (iii) faecal water content, to improve understanding of IRT-induced intestinal injury and support development of future therapeutic strategies. Anaesthetized Sprague–Dawley rats underwent in situ duodenal perfusion to quantify the effects of intravenous (i.v.) IRT on duodenal motility and blood-to-lumen clearance of ³H-mannitol (paracellular route). In separate experiments, intestinal toxicity was induced by intraperitoneal (i.p.) IRT. After 72 h, rats were sacrificed and the small intestine and colon collected for histopathological evaluation. Body weight and faecal water content were assessed. Additionally, the effects of IRT and its active metabolite SN-38 on cell viability were examined in HCT116 cells. IRT (60 mg/kg, i.v.) markedly increased duodenal motility (+ 277
