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Etoposide (VP16), used for the treatment of many carcinomas, can cause leukopenia, thrombocytopenia and hair loss. To overcome the side effects and achieve target therapy, layered ...double hydroxides (LDHs), a pH sensitive layered double hydroxide nanohybrid, was used here as a nano-carrier. The functions of LDHs-VP16 on non-small cell lung cancer (NSCLC) were firstly explored both in vitro and in vivo. In A549 cell line, LDH-VP16 induced apoptosis 2.3-fold as that of plain VP16 by targeting to mitochondrial, stocking cells in G1 phase. The cellular uptake demonstrated the delivery of LDH for VP16 to pass through the membrane and accumulate in mitochondria. As a carrier, LDH greatly decreased the liver toxicity and hematotoxicity of VP16. The detected liver parameters, including glutamic-oxaloacetic transaminase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), were all turn back to normal range after the delivery of LDH, except ALP. In vivo, LDH-VP16 reduced A549 tumor growth significantly by 60.5%, whereas native VP16 exerted no significant anticancer activity. In LDH-VP16 treated mice, the AUC was increased by 6.26 folds as the native drug, and t1/2 of LDH-VP16 was prolonged from 6.68 to 98.78h. LDH-VP16 showed a targeting effect, which largely increase the concentration in tumor and lung. The phosphorylation antibody array and Western Blot of proteins from xenografts revealed that PI3K–AKT signaling was suppressed in the LDH-VP16 treated tumor, while in VP16 treated mice, ERBB signaling pathway was involved. These results suggested that LDH-VP16 diminishes hematotoxicity, targets NSCLC tumor, performs more effectively than VP16, and different signaling pathway is involved compared to VP16.
This paper explored that nano-sized layered double hydroxide (LDH) could be used as a pH sensitive delivery system to overcome hematotoxicity and enhance the bioavailability and anticancer efficacy of etoposide (VP16) against non small cell lung cancer, which was not reported before, as the best of our knowledge. We found that the liver and hematotoxicity is nearly recovered after the loading of VP16 in pH sensitive LDH, which prongs the half time from 6.68h to 98h, helps target VP16 to tumor and lung, and protects white blood cells by its pH sensitive and nano-size property. LDH-VP16 achieve markedly performance on non-small cell lung cancer by targeting to mitochondria of A549 cells in vitro and effectively inhibiting the PI3K–AKT signaling pathway in vivo. The inhibition ratio of VP16 on A549 tumor growth is increased from less than 20% (no significance compared to control) to 60.5% after the delivery of LDH. This work provides a novel system for the safe and efficient use of etoposide on non-small cell lung cancer and explores the mechanism of the function of nano carrier in cancer therapy both in vitro and in vivo.
The optimal chemotherapy regimen administered currently with radiation in patients with stage III non-small cell lung cancer (NSCLC) remains unclear. A multicenter phase III trial was conducted to ...compare the efficacy of concurrent thoracic radiation therapy with either etoposide/cisplatin (EP) or carboplatin/paclitaxel (PC) in patients with stage III NSCLC.
Patients were randomly received 60–66 Gy of thoracic radiation therapy concurrent with either etoposide 50 mg/m2 on days 1–5 and cisplatin 50 mg/m2 on days 1 and 8 every 4 weeks for two cycles (EP arm), or paclitaxel 45 mg/m2 and carboplatin (AUC 2) on day 1 weekly (PC arm). The primary end point was overall survival (OS). The study was designed with 80% power to detect a 17% superiority in 3-year OS with a type I error rate of 0.05.
A total of 200 patients were randomized and 191 patients were treated (95 in the EP arm and 96 in the PC arm). With a median follow-up time of 73 months, the 3-year OS was significantly higher in the EP arm than that of the PC arm. The estimated difference was 15.0% (95% CI 2.0%–28.0%) andP value of 0.024. Median survival times were 23.3 months in the EP arm and 20.7 months in the PC arm (log-rank testP = 0.095, HR 0.76, 95%CI 0.55–1.05). The incidence of Grade ≥2 radiation pneumonitis was higher in the PC arm (33.3% versus 18.9%,P = 0.036), while the incidence of Grade ≥3 esophagitis was higher in the EP arm (20.0% versus 6.3%,P = 0.009).
EP might be superior to weekly PC in terms of OS in the setting of concurrent chemoradiation for unresectable stage III NSCLC.
NCT01494558.
Drug resistance has a major impact on the treatment of several cancers. This is mainly due to the overexpression of cellular drug efflux proteins. Hence, drug‐delivery systems that can avoid this ...resistance are needed. We report PR10, a progesterone‐cationic lipid conjugate, as a self‐assembling nanoaggregate that delivers a drug cargo of etoposide, a topoisomerase inhibitor, selectively to cancer cells. In this study, we observed that etoposide nanoaggregates (P : E) caused selective and enhanced toxicity in etoposide‐resistant CT26 cancer cells (IC50 9 μM) compared to when etoposide (IC50>20 μM) was used alone. Concurrently, no toxicity was observed in etoposide‐sensitive HEK293 cells for P : E treatment (IC50>20 μM). The P : E‐treated cancer cells seem to have no effect on ABCB1 expression, but etoposide‐treated cells exhibited a twofold increase in ABCB1 expression, a potent efflux protein for several xenobiotic compounds. This observation supports the notion that the enhanced toxicity of P : E nanoaggregates is due to their ability to keep the expression of ABCB1 low, thus allowing longer intracellular residence of etoposide. In a BALB/c orthotopic colorectal cancer model, the nanoaggregates led to enhanced survival (45 days) compared to etoposide‐treated mice (39 days). These findings suggest that PR10 could be used as a potential cancer‐selective etoposide delivery vehicle to treat several etoposide‐resistant cancers with fewer side effects due to the nonspecific toxicity of the drug.
Overcoming cancer's defences: Etoposide treatment causes upregulation of ABCB1 drug efflux protein in CT26 colorectal cancer cells causing etoposide resistance. However, with PR10:etoposide nanoaggregates, ABCB1 expression remains at basal level allowing etoposide to cause its effect for longer, causing increased toxicity in these cancer cells.
Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide ...and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC.
Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided
= .0048 for PFS and .0128 for OS.
Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio HR, 0.75; 95% CI, 0.61 to 0.91;
= .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98;
= .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%.
Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.
IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 PD-L1) to carboplatin ...plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden bTMB) are reported.
Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously IV, day 1) plus ET (100 mg/m
IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.
Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive
= .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.
Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.
Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide ...was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer.
In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0–2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin area under the curve 5 mg/mL per min on day 1 plus intravenous etoposide 100 mg/m2 from day 1 to day 3) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346.
Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0−37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9–5·5 vs 2·7 months, 2·3–3·2; stratified hazard ratio 0·57, 90% CI 0·41–0·73; p=0·0041). The most frequent grade 3–4 adverse events were neutropenia (18 22% of 81 patients in the topotecan group vs 11 14% of 81 patients in the combination chemotherapy group), thrombocytopenia (29 36% vs 25 31%), anaemia (17 21% vs 20 25%), febrile neutropenia (nine 11% vs five 6%), and asthenia (eight 10% vs seven 9%). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group.
Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer.
Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).
In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also ...more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear.
We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed.
Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval CI, 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.
The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).
Mesenchymal stromal cells (MSCs) play a crucial role in advancing our understanding of regenerative medicine and cell-based therapies and are found in various tissues such as bone marrow (BM), ...adipose tissue, umbilical cord blood (CB) or umbilical cord (UC). They have a remarkable potential for tissue repair (BM- and CB-MSCs for bone and cartilage) and immunomodulation through cytokine secretion. MSC multipotency in vitro (restricted in vivo) is one of the key reasons for their significance and is consequently an important functionality marker, although the transcriptome signature differs among the tissues.
MSCs can be impacted by environmental mutagens i.e. methylating agents such as nitrosamines or anti-cancer agents i.e. the topoisomerase II inhibitor etoposide, both inducing DNA double-strand breaks. The effects by which the DNA damage repair mechanisms (DDR) are triggered and how this influences cell differentiation remain unknown.
Neonatal CB-MSCs and adult BM-MSCs were treated with N-nitroso-methyl-urea (MNU) or etoposide before the induction of osteogenic, adipogenic or chondrogenic differentiation (d0) or after 7 days of differentiation (d7). The expression of several DNA damage repair genes and specific differentiation-related genes was analyzed after genotoxic damage in a biological age-dependent manner by RT-qPCR. Induced pluripotent stem cells (iPSCs) were used as a negative control. In addition, multipotentcy of MSCs generated from iPSCs (iMSCs) was investigated and compared to MSCs from other sources revealing a different transcriptome signature.
Besides substantially affecting cell proliferation, MNU treatment mainly led to p53 and p21 upregulation, thus leading to increased apoptosis levels and a disturbed cell cycle distribution (increased subG1-phase, decreased S-phase).
MNU and etoposide treatment at d0 led to RUNX2 downregulation with a complete abrogation of osteogenesis and partially affected adipogenesis with no significant differences in PPARγ expression. Treatment at d7 however, did not have any effect on MSC multipotency. Furthermore, MNU treatment at d0 had a negative impact on chondrogenic condensation especially of BM-MSCs and an overall delayed chondrogenic differentiation reflected by a delayed upregulation of COL10A1, ACAN, SOX9 and FOSL2.
These results show that a comprehensive analysis of DDR at several differentiation endpoints should be implemented in the test systems, preclinical safety and toxicity evaluation studies.
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•Etoposide-polyamine hybrid compounds are strong topoisomerase II poisons.•Hybrid compounds are more active against topoisomerase II than etoposide.•Hybrid compounds display higher ...activity toward topoisomerase IIβ than IIα.•Enhanced specificity may result from interactions with Gln778 in topoisomerase IIβ.
Etoposide is an anticancer drug that acts by inducing topoisomerase II-mediated DNA cleavage. Despite its wide use, etoposide is associated with some very serious side-effects including the development of treatment-related acute myelogenous leukemias. Etoposide targets both human topoisomerase IIα and IIβ. However, the contributions of the two enzyme isoforms to the therapeutic vs. leukemogenic properties of the drug are unclear. In order to develop an etoposide-based drug with specificity for cancer cells that express an active polyamine transport system, the sugar moiety of the drug has been replaced with a polyamine tail. To analyze the effects of this substitution on the specificity of hybrid molecules toward the two enzyme isoforms, we analyzed the activity of a series of etoposide-polyamine hybrids toward human topoisomerase IIα and IIβ. All of the compounds displayed an ability to induce enzyme-mediated DNA cleavage that was comparable to or higher than that of etoposide. Relative to the parent drug, the hybrid compounds displayed substantially higher activity toward topoisomerase IIβ than IIα. Modeling studies suggest that the enhanced specificity may result from interactions with Gln778 in topoisomerase IIβ. The corresponding residue in the α isoform is a methionine.
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