Comparative analysis of immunological changes following realgar and arsenic trioxide treatments in a murine model of myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.

Arsenic-induced neurotoxicity in patients with acute promyelocytic leukaemia.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

Alternate application of all-trans-retinoic acid and arsenic trioxide combined with idarubicin/daunorubicin in treatment of acute promyelocytic leukemia.

The present study aimed to investigate the efficacy and safety for alternate application of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combined with idarubicin (IDA)/daunorubicin (DNR) in treatment of acute promyelocytic leukemia (APL). A total of 72 ALP patients were divided into the low/medium risk and high risk groups according to the WBC and PLT levels. All APL patients received induction therapy, consolidation therapy and maintenance therapy in treatment under careful nursing monitoring. The complete response (CR) rate was 87.5% (63/72), with 95.12% (39/41) in the low/medium risk group, which was markedly higher than the 77.42% (24/31) high risk group. The PML/RAR α fusion negative rate was also markedly higher in the low/medium risk group (95.12%, 39/41) than the high risk group (77.42%, 24/31). The duration for PML/RAR α fusion negative was also significantly shorter in the low/medium risk group. Recurrence was found in cases in the low/medium risk group, markedly lower than cases in the high risk group. The overall survival (OS) time was markedly longer in low/medium risk patients high. Alternate application of the combination strategy could achieve well CR rate with less complications. And patients with low/medium risk had better clinical outcomes and prognosis than high risk patients.

Improved Outcomes with Induction Chemotherapy Combined with Arsenic Trioxide in Stage 4 Neuroblastoma: A Case Series.

Objective: The apoptotic and cytotoxic effects of arsenic trioxide (ATO) makes it a potentially suitable agent for the treatment of patients with neuroblastoma with poor prognosis; therefore, we try to evaluate the effectiveness and safety of ATO combined with reinduction/induction chemotherapy in children with recurrent/refractory or newly diagnosed stage 4 neuroblastoma. Methods: Retrospective analysis was performed on seven pediatric patients with recurrent /refractory or newly diagnosed stage 4 neuroblastoma treated with traditional reinduction/induction chemotherapy combined with ATO. Results: A total of 7 patients were treated synchronously with ATO and chemotherapy for up to nine courses; all patients received conventional chemotherapy plus a 0.16 mg/kg/day dose of intravenous ATO during reinduction/induction chemotherapy. Treatment was effective in five patients and ineffective in the other two patients. The overall response rate was 71.43% (5 of 7). The side effects of the ATO combination were minor, whereby only treatment in one patient was terminated at the sixth course due to a prolonged QT interval (0.51 s), which returned to normal after symptomatic treatment. Conclusions: ATO can be safely and effectively combined with chemotherapy drugs as a potential alternative means of treatment for high-risk stage 4 neuroblastoma, and we have observed that ATO can restore the sensitivity of chemotherapy in some patients who were resistant to previous chemotherapy. Further investigations and clinical data are required to confirm these observations.

Formulation Comprising Arsenic Trioxide and Dimercaprol Enhances Radiosensitivity of Pancreatic Cancer Xenografts.

OBJECTIVE: To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts. METHODS: Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays. RESULTS: Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups (P < 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) (P < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT. CONCLUSION: These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.

All-trans Retinoic Acid, Arsenic Trioxide, and Anthracycline-based Chemotherapy Improves Outcome in Newly Diagnosed Acute Promyelocytic Leukemia Regardless of FLT3-ITD Mutation Status.

All-trans retinoic acid (ATRA) and pre-upfront arsenic trioxide (ATO) have revolutionized the therapy of acute promyelocytic leukemia (APL). However, internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations is associated with increased risk of relapse. The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA, idarubicin (IDA) and/or ATO, followed by ATRA plus ATO along with anthracycline, as consolidation therapy. A total of 72 patients newly diagnosed with APL were included in this study. 83.3% of the patients achieved complete remission (CR) after induction therapy. FLT3-ITD mutations were detected in 16 (22.2%) patients and closely related to bcr-3 PML-RARa transcript (P<0.001). The 5-year overall survival (OS) rate was 100% in both FLT3-ITDpositive and FLT3-ITDnegative groups, and there was no significant difference in 5-year event-free survival (EFS) between the two groups (78.3% vs. 83.3%, P=0.85). ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.

Effect of renal impairment on arsenic accumulation, methylation capacity, and safety in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5-4 fold in moderate and severe renal impairment groups, iAs increased 1.3-1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment.Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.

Arsenic Combined With All-Trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia: Report From the CCLG-APL2016 Protocol Study.

PURPOSE: Arsenic combined with all-trans retinoic acid (ATRA) is the standard of care for adult acute promyelocytic leukemia (APL). However, the safety and effectiveness of this treatment in pediatric patients with APL have not been reported on the basis of larger sample sizes. METHODS: We conducted a multicenter trial at 38 hospitals in China. Patients with newly diagnosed APL were stratified into two risk groups according to baseline WBC count and FLT3-ITD mutation. ATRA plus arsenic trioxide or oral arsenic without chemotherapy were administered to the standard-risk group, whereas ATRA, arsenic trioxide, or oral arsenic plus reduced-dose anthracycline were administered to the high-risk group. Primary end points were event-free survival and overall survival at 2 years. RESULTS: We enrolled 193 patients with APL. After a median follow-up of 28.9 months, the 2-year overall survival rate was 99% (95% CI, 97 to 100) in the standard-risk group and 95% (95% CI, 90 to 100) in the high-risk group (P = .088). The 2-year event-free survival was 97% (95% CI, 93 to 100) in the standard-risk group and 90% (95% CI, 83 to 96) in the high-risk group (P = .252). The plasma levels of arsenic were significantly elevated after treatment, with a stable effective level ranging from 42.9 to 63.2 ng/mL during treatment. In addition, plasma, urine, hair, and nail arsenic levels rapidly decreased to normal 6 months after the end of treatment. CONCLUSION: Arsenic combined with ATRA is effective and safe in pediatric patients with APL, although long-term follow-up is still needed.

Arsenic trioxide-loaded CalliSpheres: In vitro study of drug release and antitumor activity, and in vivo study of pharmacokinetics, treatment efficacy and safety in liver cancer.

The aim of the present study was to investigate the arsenic trioxide (ATO) loading/releasing efficiency of CalliSphere beads (CBs), as well as the in vitro anticancer activity, in vivo pharmacokinetics, treatment efficacy and safety of ATO-eluting CBs in liver cancer. The ATO loading and releasing efficiencies in CBs were evaluated. Furthermore, cell viability, invasion, apoptosis, VEGF expression and MMP9 expression were determined in liver cancer cells treated with ATO-eluting CBs or ATO solution. Rabbit liver models were established and underwent TACE with ATO-eluting CBs or ATO/lipiodol emulsion. Subsequently, their ATO pharmacokinetics were determined and macroscopic/microscopic examinations were conducted. In vitro, CB-loaded ATO increased during 40 min with an optimal loading efficiency of 23.0±2.5%, and released ATO rapidly within the first 30 min (31.40±10.0%) then slowed down within the latter 48 h (47.20±4.70%). ATO-eluting CBs exhibited decreased cell viability to some extent and similar invasive cell count, apoptosis rate, VEGF and MMP9 levels compared with ATO solution at various concentrations and time-points. In vivo, ATO concentration was lower in plasma, but higher in tumor tissues, and necrosis was more complete in tumor tissue while milder in normal liver parenchyma after rabbit liver was embolized with ATO-eluting CBs compared with ATO/lipiodol emulsion. ATO-eluting CBs may be a novel and promising therapeutic option in treating liver cancer.

Characteristics and clinical influence factors of arsenic species in plasma and their role of arsenic species as predictors for clinical efficacy in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) is successfully applied to treat acute promyelocytic leukemia (APL). Arsenic species levels in blood are critical to reveal metabolic mechanism and relationship between arsenic species and clinical response. Characteristics and influence factors of arsenic species in APL patients have not been studied.Methods: 305 plasma samples from APL patients treated with ATO were analyzed using HPLC-HG-AFS. Trough concentration (Ctrough), distribution, methylation levels of arsenic species were evaluated. The influence factors on arsenic species levels of plasma and association between arsenic concentrations and clinical efficacy were explored.Results: Ctrough of arsenic in effective treatment groups provide basis for defining the target range of arsenic plasma concentrations in APL patients treated with ATO. Distribution trends: DMAV > AsIII, MMAV> AsV (p < 0.0001) for continuous slow-rate (CS) infusion and DMAV > MMAV > AsIII > AsV (p < 0.0001) for conventional infusion. Infusion methods and combined medication may affect arsenic metabolism. There was a weak correlation between ATO dose and plasma Ctrough of arsenic species. Ctrough of plasma arsenic species had predictive value for treatment efficacy.Conclusion: Arsenic concentration monitoring in APL patients treated with ATO is required. These findings are critical to optimize treatment outcomes of ATO therapy.

Safety and efficacy of different doses of anthracyclines combined with arsenic trioxide and all-trans retinoic acid in the treatment of de novo acute promyelocytic leukemia.

OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of different doses of anthracyclines combined with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) for induction in newly diagnosed acute promyelocytic leukemia (APL). METHODS: One hundred and forty patients were included between January 2011 and December 2017. Seventy patients received low dose anthracycline, ATO and ATRA for induction chemotherapy; and other seventy patients received standard dose anthracycline, ATO and ATRA for induction chemotherapy. RESULTS: The outcomes of both groups were similar: low dose group versus standard dose group: early mortality 5.7% vs. 10.0% (P = 0.532), disease-free survival (DFS), probabilities of overall-survival (OS) at 2 years 94.6% vs. 95.1% (P = 0.657), 92.8% vs. 88.2% (P = 0.951), respectively. However, the standard-dose group was associated with a longer duration of neutropenia (p < 0.001) and thrombocytopenia (p < 0.001), more volumes of platelets (p = 0.037) and red blood cell transfusions (p < 0.001), and a higher rate of infections (p = 0.042). CONCLUSION: Low-dose group achieves outcomes similar to those of standard dose group for APL patients, but the low-dose group may be even safer than standard-dose group. So the low-dose anthracycline may be a better choice for newly diagnosed APL patients.

Magnesium Isoglycyrrhizinate Alleviates Arsenic Trioxide-Induced Cardiotoxicity: Contribution of Nrf2 and TLR4/NF-κB Signaling Pathway.

PURPOSE: Magnesium isoglycyrrhizinate (MgIG), a single stereoisomer magnesium salt of glycyrrhizic acid, has beneficial effects on the cardiovascular system through anti-inflammatory, anti-oxidation, and anti-apoptotic actions. However, MgIG has not been shown to provide protection against cardiotoxicity induced by arsenic trioxide (ATO). This study aims to demonstrate the protection of MgIG against ATO-induced cardiac toxicity in mice and to investigate the underlying mechanism. METHODS: A mouse cardiotoxicity model was established by administering 5 mg/kg ATO for 7 days. MgIG used in conjunction with the ATO to assess its cardioprotection. RESULTS: MgIG administration could significantly reduce reactive oxygen species generation and the changes in tissue morphology. Also, MgIG administration increased the activity of antioxidase, such as superoxide dismutase, catalase, and glutathione peroxidase, and reduced malondialdehyde content and pro-inflammatory cytokine levels. Western blotting showed decreased expression of Bcl-2 associated X protein and Caspase-3, with increased expression of B-cell lymphoma 2. Importantly, MgIG administration increased nuclear factor-erythroid-2-related factor 2 (Nrf2) expression, while the expressions of nuclear factor kappa-B (NF-κB) and toll-like receptor-4 (TLR4) were significantly decreased. CONCLUSION: Our data showed that MgIG alleviates ATO-induced cardiotoxicity, which is associated to the anti-inflammation, anti-oxidation, and anti-apoptosis action, potentially through activation of the Nrf2 pathway and suppression of the TLR4/NF-κB pathway.

Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically.

OBJECTIVE: Differentiation-inducing therapy for tumors is a strategy that aims to induce the differentiation and maturation of cancer stem cells (CSCs). The differentiation-inducing capacity of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC) and the underlying mechanism were previously unknown. METHODS: In the present study, we explored the ATO-induced differentiation of CSCs in HCC by detecting the expression of CSC-related markers and tumorigenicity variation in vivo and in vitro. We developed a combined chemotherapeutic approach to HCC by characterizing the effects of combinatorial treatment with 5-fluorouracil (5-FU)/cisplatin and ATO in vitro and in patient-derived xenograft models. Changes in gene expression patterns were investigated by gene microarray analysis. RESULTS: ATO effectively induced differentiation of CSCs by downregulation of CSC-related genes and suppression of tumorigenicity capability. Combinatorial treatment with ATO and 5-FU/cisplatin significantly enhanced therapeutic effects in HCC cells compared with the treatment with 5-FU/cisplatin alone. Synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways by ATO and 5-FU/cisplatin is a potential molecular mechanism underlying the differentiation effect. CONCLUSIONS: ATO induced the differentiation of HCC CSCs and potentiated the cytotoxic effects of 5-FU/cisplatin through synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways. These results offer new insights for the clinical treatment of HCC.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Preparation of PLGA microspheres loaded with 10-hydroxycamptothecin and arsenic trioxide and their treatment for rabbit hepatocellular carcinoma.

OBJECTIVE: This study aims to study the preparation method of arsenic trioxide (As2O3) polylactic-co-glyconlic acid (PLGA) microspheres and 10-hydroxycamptothecin (HCPT) PLGA microspheres and explore their therapeutic effects as embolic agents for VX2 hepatocellular carcinoma in rabbits. METHODS: As2O3 and HCPT PLGA microspheres were prepared by multiple emulsion solvent evaporation method. Scanning electron microscopy (SEM) and particle size distribution were used to analyze the morphology, the drug sustained release ability was observed by the release of microspheres in vitro. The rabbit model of VX2 hepatocellular carcinoma was established and the hepatocellular carcinoma was treated with combined microspheres. The therapeutic effects were detected by qPCR, western blotting, HE staining and immunohistochemical methods. RESULTS: The PLGA microspheres loaded with As2O3 and HCPT were successfully prepared by optimizing the ratio. The particle size was between 30 and 50 µm. In vitro release results showed that PLGA microspheres loaded with As2O3 released completely in 10 days and PLGA microspheres loaded with HCPT released completely in 12 days. Western blotting and qPCR results showed that the expression of ALDH1A1 and Nanog decreased significantly in treatment group. HE staining and immunohistochemical analysis showed that the expression of CD31, HIF and VEGF decreased significantly and the apoptosis of tissues was obvious. CONCLUSION: The combination of As2O3 and HCPT PLGA microspheres as embolization for VX2 hepatocellular carcinoma in rabbits has significant therapeutic effect.

Effects of different autophagy inhibitors on sensitizing KG-1 and HL-60 leukemia cells to chemotherapy.

A little number of current autophagy inhibitors may have beneficial effects on the acute myeloid leukemia (AML) patients. However, there is a strong need to figure out which settings should be activated or inhibited in autophagy pathway to prevail drug resistance and also to improve current treatment options in leukemia. Therefore, this study aimed to compare the effects of well-known inhibitors of autophagy (as 3-MA, BafA1, and HCQ) in leukemia KG-1 and HL-60 cells exposed to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Cell proliferation and cytotoxicity of cells were examined by MTT assay. Autophagy was studied by evaluating the development of acidic vesicular organelles, and the autophagosomes formation was investigated by acridine orange staining and transmission electron microscopy. Moreover, the gene and protein expressions levels of autophagy markers (ATGs, p62/SQSTM1, and LC-3B) were also performed by qPCR and western blotting, respectively. The rate of apoptosis and cell cycle were evaluated using flow cytometry. We compared the cytotoxic and apoptotic effects of ATO and/or ATRA in both cell lines and demonstrated that some autophagy markers upregulated in this context. Also, it was shown that autophagy blockers HCQ and/or BafA1 could potentiate the cytotoxic effects of ATO/ATRA, which were more pronounced in KG-1 cells compared to HL-60 cell line. This study showed the involvement of autophagy during the treatment of KG-1 and HL-60 cells by ATO/ATRA. This study proposed that therapy of ATO/ATRA in combination with HCQ can be considered as a more effective strategy for targeting leukemic KG-1 cells.

Chemoembolizing hepatocellular carcinoma with microsphere cored with arsenic trioxide microcrystal.

Chemoembolization for hepatocellular carcinoma (HCC) is often suboptimal due to multiple involved signaling and lack of effective drugs. Arsenic trioxide (ATO) is a potent chemotherapeutic agent, which can target multiple signaling and have substantial efficacy on HCC. However, its usage is limited due to systemic toxicity. Using ATO-eluting beads/microspheres for chemoembolization can have locoregional drug delivery and avoid systemic exposure but will require high drug load, which has not been achieved due to low solubility of ATO. Through an innovative approach, we generated the transiently formed ATO microcrystals via micronization and stabilized these microcrystals by solvent exchange. By encapsulating ATO microcrystals, but not individual molecules, with poly(lactide-co-glycolic acid) (PLGA), we developed microspheres cored with extremely high dense ATO. The molar ratio between ATO and PLGA was 157.4:1 and drug load was 40.1%, which is 4-20 fold higher than that of reported ATO nano/microparticles. These microspheres sustainably induced reactive oxygen species, apoptosis, and cytotoxicity on HCC cells and reduced tumor growth by 80% via locoregional delivery. Chemoembolization on mice model showed that ATO-microcrystal loaded microspheres, but not ATO, inhibited HCC growth by 60-75%, which indicates ATO within these microspheres gains the chemoembolizing function via our innovative approach.

Effects of arsenic trioxide combined with platinum drugs in treatment of cervical cancer: A protocol for systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Cervical cancer is the second largest tumor disease threatening female reproductive tract health. AS2O3 is a multi-directional and multi-target anti-cervical cancer drug. It can be combined with platinum drugs to treat cervical cancer. The literatures of AS2O3 combined with platinum drugs related to cervical cancer have shown inconsistent results, and there is currently no high quality of systematic review to evaluate the effects of AS2O3 combined with platinum drugs in cervical cancer patients. METHODS AND ANALYSIS: English and Chinese literature about AS2O3 combined with platinum drugs treatment for cervical cancer published before August 31, 2020 will be systematic searched in PubMed, Embase, Web of Science, Cochrane Library, Open Grey, Clinicaltrials.gov, Chinese Clinical Trial Registry, WANFANG, VIP Chinese Science and Technology Journal Database, CNKI, Chinese biomedical document service system (SinoMed). Only randomized controlled trials (RCTs) of patients with cervical cancer will be included. Literature screening, data extraction, and the assessment of risk of bias will be independently conducted by 2 reviewers, and the 3rd reviewer will be consulted if any different opinions existed. Clinical total effective rate, adverse events, SCCAg, CYFRA21-1, quality of life, and immune function will be evaluated. Systematic review and meta-analysis will be produced by RevMan 5.3 and Stata 14.0. This protocol reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) statement, and we will report the systematic review by following the PRISMA statement. RESULTS: The current study is a protocol for systematic review and meta-analysis without results, and data analysis will be carried out after the protocol. We will share our findings in the fourth quarter of 2021. CONCLUSION: Efficacy and safety of AS2O3 combined with platinum drugs in the treatment of cervical cancer will be assessed. The results will be published in a public issue journal to provide evidence-based medical evidence for Obstetrician and Gynecologists to make clinical decisions. ETHICS AND DISSEMINATION: Ethical approval is not required as the review is a secondary study based on published literature. The results of the study will be published in peer-reviewed publications and disseminated electronically or in print. PROTOCOL REGISTRATION NUMBER: INPLASY202080130.