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"A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle." (MeSH 2013)

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Latest Research Publications

Web Resources: Etoposide (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Liu X, Luo L, Qi P, et al.
A Comprehensive Preclinical Evaluation of Intravenous Etoposide Lipid Emulsion.
Pharm Res. 2019; 36(7):96 [PubMed] Related Publications
PURPOSE: Etoposide is one of the principal chemotherapeutic agents used for the treatment of small cell lung cancer (SCLC). There are some disadvantages of currently available etoposide injections (EI) such as low LD
METHODS: ELE was prepared through high-pressure homogenization method, and a series of evaluations such as encapsulation efficiency (EE%), in vitro release, stability studies, pharmacokinetics study, safety assessment and pharmacodynamic study were systematically performed.
RESULTS: ELE had high EE% and good stability. Pharmacokinetics study revealed ELE had a longer T
CONCLUSIONS: Unlike EI, ELE could further increase the dose, which endowed etoposide with a greater potential for cytotoxic agent. LE is a promising delivery system for etoposide.

Yoon SB, Park HR
Arctigenin Inhibits Etoposide Resistance in HT-29 Colon Cancer Cells during Microenvironmental Stress.
J Microbiol Biotechnol. 2019; 29(4):571-576 [PubMed] Related Publications
Microenvironmental stress, which is naturally observed in solid tumors, has been implicated in anticancer drug resistance. This tumor-specific stress causes the degradation of topoisomerase IIα, rendering cells resistant to topoisomerase IIα-targeted anticancer agents. In addition, microenvironmental stress can induce the overexpression of 78kDa glucose regulated protein (GRP78), which can subsequently block the activation of apoptosis induced by treatment with anticancer agents. Therefore, inhibition of topoisomerase IIα degradation and reduction in GRP78 expression may be effective strategies for inhibiting anticancer drug resistance. In this study, we investigated the active compound arctigenin, which inhibited microenvironmental stress-induced etoposide resistance in HT-29 cells. Arctigenin was also highly toxic to etoposide-resistant HT-29 cells, with an IC

Özkan A, Atar N, Yola ML
Enhanced surface plasmon resonance (SPR) signals based on immobilization of core-shell nanoparticles incorporated boron nitride nanosheets: Development of molecularly imprinted SPR nanosensor for anticancer drug, etoposide.
Biosens Bioelectron. 2019; 130:293-298 [PubMed] Related Publications
An effective SPR nanosensor based on core-shell nanoparticles (Ag@AuNPs) incorporated hexagonal boron nitride (HBN) nanosheets and molecularly imprinted polymer (MIP) was presented for etoposide (ETO) detection. Scanning electron microscope (SEM), transmission electron microscope (TEM), x-ray diffraction (XRD) method, cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), fourier transform infrared (FTIR) spectroscopy and atomic force microscopy (AFM) methods were utilized for all characterizations of nanomaterials and polymer surfaces. ETO imprinted SPR nanosensor based on Ag@AuNPs-HBN nanocomposite was developed in the presence of poly(2-hydroxyethyl methacrylate-methacryloylamidoglutamic acid) [p(HEMA-MAGA)]. The results of the study have revealed that 0.001-1.00 ng mL

Cai Y, Wan L, Yang J, et al.
High-dose etoposide could discriminate the benefit from autologous peripheral blood stem cell transplantation in the patients with refractory diffuse large B cell lymphoma.
Ann Hematol. 2019; 98(4):823-831 [PubMed] Free Access to Full Article Related Publications
To evaluate the strategy of using high-dose etoposide mobilization followed by autologous peripheral blood stem cell transplantation (APBSCT) in patients with diffuse large B cell lymphoma (DLBCL) refractory to rituximab-based chemotherapy. Forty patients with refractory DLBCL were treated with high-dose etoposide for stem cell mobilization. All patients were in progressive disease (PD) prior to mobilization and underwent high-dose chemotherapy followed by APBSCT. Successful PBSC mobilization was achieved in all patients. Twenty-three patients (57.5%) showed a clinical response to high-dose etoposide. After APBSCT, 17 patients (42.5%) achieved CR. The 2-year progression-free (PFS) and overall survival (OS) rate were higher in patients responding to high-dose etoposide (64.1% and 77.7%) compared to those without response (11.8% and 11.8%; P < 0.001 for both). The response to high-dose etoposide mobilization therapy was an independent prognostic factor for CR achievement, PFS and OS after APBSCT. High-dose etoposide mobilization chemotherapy followed by APBSCT could rescue a proportion of patients with refractory DLBCL who responded to etoposide mobilization regimen.

Saroj S, Rajput SJ
Etoposide encased folic acid adorned mesoporous silica nanoparticles as potent nanovehicles for enhanced prostate cancer therapy: synthesis, characterization, cellular uptake and biodistribution.
Artif Cells Nanomed Biotechnol. 2018; 46(sup3):S1115-S1130 [PubMed] Related Publications
The present research was motivated by the dire need to design a targeted and safe Nano-vehicle for delivery of Etoposide (ETE), which would be tolerant of normal cells and exclusively toxic to prostate cancer cells. The folic acid functionalized mesoporous silica nanoparticles (MSNs) constructed by using a facile method acting as a unique selective platform for ETE delivery for effective prostate cancer treatment. FA@MSNs possessed good payload and encouraging in vitro release was obtained for ETE caged inside FA-MSNs compared with ETE-MSNs alone. Further, FA@MSNs exhibited an improved blood compatibility compared with pristine silica. The cellular analysis on PC-3 and LNCaP cell lines unveiled an excellent performance of cytotoxicity. Apoptosis assay confirmed a programmed cell death ruling out necrosis. Most importantly enhanced cellular uptake was obtained for FITC#FA@MSNs. In addition, pharmacokinetic and biodistribution studies in healthy mice indicated a favourable longer circulation time and reduced plasma elimination rate for ETE/FA@MSNs than free ETE. Further, histological and cell cytotoxicity results proved that nanocarriers themselves were safe without any noticeable toxicity. The results showed that FA@MSNs were ideal candidates for safe and effective delivery of ETE and hold a substantial potential as drug delivery vehicles for enhanced prostate cancer therapy.

Tosca EM, Pigatto MC, Dalla Costa T, Magni P
A Population Dynamic Energy Budget-Based Tumor Growth Inhibition Model for Etoposide Effects on Wistar Rats.
Pharm Res. 2019; 36(3):38 [PubMed] Related Publications
PURPOSE: This work aimed to develop a population PK/PD tumor-in-host model able to describe etoposide effects on both tumor cells and host in Walker-256 tumor-bearing rats.
METHODS: Etoposide was investigated on thirty-eight Wistar rats randomized in five arms: two groups of tumor-free animals receiving either placebo or etoposide (10 mg/kg bolus for 4 days) and three groups of tumor-bearing animals receiving either placebo or etoposide (5 or 10 mg/kg bolus for 8 or 4 days, respectively). To analyze experimental data, a tumor-in-host growth inhibition (TGI) model, based on the Dynamic Energy Budget (DEB) theory, was developed. Total plasma and free-interstitial tumor etoposide concentrations were assessed as driver of tumor kinetics.
RESULTS: The model simultaneously describes tumor and host growths, etoposide antitumor effect as well as cachexia phenomena related to both the tumor and the drug treatment. The schedule-dependent inhibitory effect of etoposide is also well captured when the intratumoral drug concentration is considered as the driver of the tumor kinetics.
CONCLUSIONS: The DEB-based TGI model capabilities, up to now assessed only in mice, are fully confirmed in this study involving rats. Results suggest that well designed experiments combined with a mechanistic modeling approach could be extremely useful to understand drug effects and to describe all the dynamics characterizing in vivo tumor growth studies.

Kuo YC, Chang YH, Rajesh R
Targeted delivery of etoposide, carmustine and doxorubicin to human glioblastoma cells using methoxy poly(ethylene glycol)‑poly(ε‑caprolactone) nanoparticles conjugated with wheat germ agglutinin and folic acid.
Mater Sci Eng C Mater Biol Appl. 2019; 96:114-128 [PubMed] Related Publications
Wheat germ agglutinin (WGA) and folic acid (FA)-grafted methoxy poly(ethylene glycol) (MPEG)‑poly(ε‑caprolactone) (PCL) nanoparticles (WFNPs) were applied to transport anticancer drugs across the blood-brain barrier and treat glioblastoma multiforme (GBM). PCL was copolymerized with MPEG, and MPEG-PCL NPs were stabilized with pluronic F127 using a microemulsion-solvent evaporation technique and crosslinked with WGA and FA. The targeting ability of WFNPs loaded with etoposide (ETO), carmustine (BCNU) and doxorubicin (DOX) was investigated via the binding affinity of drug-loaded NP formulations to N‑acetylglucosamine expressed in human brain microvascular endothelial cells and to folate receptor in malignant U87MG cells. We found that a shorter PCL chain in drug-loaded MPEG-PCL NPs yielded a smaller average size of the particles. An increase in PCL chain length (stronger hydrophobicity) enhanced drug entrapment efficiencies in MPEG-PCL NPs, and reduced drug-releasing rates from NP formulations. In addition, anti-proliferative activity against U87MG cells for the 3 drugs followed the order of WFNPs > FA-grafted NPs > WGA-grafted NPs > MPEG-PCL NPs. Immunofluorescence staining revealed that the ligands of drug-loaded WFNPs connected to N‑acetylglucosamine and folate receptor with the help of surface WGA and FA. WFNPs carrying ETO, BCNU and DOX acted as dual-targeting nanocarriers, and their use can be a promising approach to inhibiting GBM growth in the brain.

Damiani E, Solorio JA, Doyle AP, Wallace HM
How reliable are in vitro IC
Toxicol Lett. 2019; 302:28-34 [PubMed] Related Publications
Increasing evidence shows that discrepancies exist among in vitro cytotoxicity methods resulting in unreliable drug toxicity profiles. This is particularly criticial for cell lines such as gliomas which are histologically and genetically heterogeneous. The high level of variation in these cells makes comparative analysis difficult and is a severe limitation for the usefulness of high-throughput screening methods. Here we examine variations between four conventional in vitro cytotoxicity assays (MTT, Alamar Blue, Acid Phosphatase and Trypan Blue) for assessing the viable cell number following treatment of two human glioblastoma cell lines (U87MG and U373MG) with different chemical agents (carboplatin, etoposide, paraquat). The variations in IC

Popova P, Notabi MK, Code C, et al.
Co-delivery of siRNA and etoposide to cancer cells using an MDEA esterquat based drug delivery system.
Eur J Pharm Sci. 2019; 127:142-150 [PubMed] Related Publications
Cancer has become the leading cause of death in many countries. Chemotherapy is a key component in the treatment of most cancers but has limited efficacy if the cancer develops resistance to the treatment over time and recur. RNA interference may be used to reduce the production of the proteins responsible for chemotherapeutic resistance. Small interfering RNAs (siRNA) may be used to induce RNA interference but the application of these to cancer cells is hampered by poor serum stability and delivery to their cytoplasmic site of activity. This work introduces a novel nanoparticle delivery system for siRNA and hydrophobic anticancer drugs. The system is based on a cationic MDEA esterquat, which is widely and safely used in personal care products but has never been assessed for drug delivery applications. We show that MDEA forms spherical compact nanoparticles when combined with siRNA that delivers the siRNA to cancer cells where it induces gene silencing. By combining DOPE and MDEA in ratios of 2:1 and 3:1, even higher gene silencing levels (>90%) may be achieved. The system is capable of combinational therapy by co-delivering siRNA and the chemotherapeutic drug etoposide to cancer cells and these particles both induce gene silencing and chemotherapy induced cell death. We believe the present system may be used for intra-tumoral injection of chemotherapy in solid chemotherapy resistant tumors and for systemic delivery with further development.

Cabel L, Carton M, Cheaib B, et al.
Oral etoposide in heavily pre-treated metastatic breast cancer: results from the ESME cohort and comparison with other chemotherapy regimens.
Breast Cancer Res Treat. 2019; 173(2):397-406 [PubMed] Related Publications
INTRODUCTION: HER2-negative metastatic breast cancer (MBC) is a common setting in which chemotherapy could be effective even in later lines of treatment. Oral etoposide has demonstrated clinical activity in this setting in small-scale studies, but its efficacy has not been compared to that of other chemotherapy regimens.
METHODS: We used the ESME database (Epidemiological Strategy and Medical Economics), a real-life national French multicentre cohort of MBC patients initiating therapy between 1 January 2008 to 31 December 2014. HER2-negative MBC patients who received oral etoposide as > 3rd chemotherapy line and for more than 14 days were included. Primary objective was progression-free survival (PFS); secondary objectives were overall survival (OS), and propensity-score matched Cox models including comparison with other therapies in the same setting.
RESULTS: Three hundred forty-five out of 16,702 patients received oral etoposide and 222 were eligible. Median PFS was 3.2 months [95% CI 2.8-4] and median OS 7.3 months [95% CI 5.7-10.3]. Median PFS did not significantly differ according to the therapeutic line. The only prognostic factor for both PFS and OS was the MBC phenotype (hormone receptor-positive versus triple-negative, HR = 0.71 [95% CI 0.52-0.97], p = 0.028 for PFS and HR = 0.65 [0.46-0.92], p = 0.014 for OS). After matching for the propensity score, no differential effect on PFS or OS was observed between oral etoposide and other chemotherapy regimens administered in the same setting (HR = 0.94 [95% CI 0.77-1.15], p = 0.55 for PFS and HR = 1.10 [95% CI 0.88-1.37], p = 0.40 for OS).
CONCLUSION: Oral etoposide retains some efficacy in selected heavily pre-treated patients with HER2-negative MBC, with the advantages of oral administration.

Hidaka T, Okuzumi S, Matsuhashi A, et al.
Large Cell Neuroendocrine Carcinoma of the Mediastinum Successfully Treated with Systemic Chemotherapy after Palliative Radiotherapy.
Intern Med. 2019; 58(4):563-568 [PubMed] Free Access to Full Article Related Publications
Large cell neuroendocrine carcinoma (LCNEC) is a highly malignant cancer originally found in lung in 1991. In extremely rare occasions, primary LCNEC is found in the mediastinum; approximately 40 of such cases have been reported. Due to the limited number of reported cases, a standardized treatment protocol has yet to be established. We report a case of a 66-year-old woman with primary mediastinal LCNEC who presented with superior vena cava syndrome. Emergent radiotherapy was performed, followed by systemic chemotherapy with cisplatin and etoposide, which resulted in a dramatic tumor reduction. This is the first report describing the achievement of a complete response after systemic chemotherapy in a patient with primary LCNEC.

Leon-Rodriguez E, Rivera-Franco MM, Lacayo-Leñero D, et al.
First - line, non - cryopreserved autologous stem cell transplant for poor - risk germ - cell tumors: Experience in a developing country.
Int Braz J Urol. 2019 Jan-Feb; 45(1):74-82 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The current first - line treatment for non - seminomatous germ cell tumor (NSGCT) consists of four cycles of cisplatin, etoposide, and bleomycin (BEP), which results in 5 - year overall survival < 60% in patients with poor - risk features. Autologous hematopoietic stem cell transplantation (auto - HSCT) as a method for overcoming high toxicity after high dose chemotherapy (HDC) has been explored in different solid tumors, but has remained standard practice only for NSGCT. Our objective was to describe outcomes of patients with poor - risk NSGCT who underwent first - line autologous HSCT in a tertiary center in Mexico.
PATIENTS AND METHODS: Twenty nine consecutive patients with NSGCT who received first - line, non - cryopreserved autologous HSCT at the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City, Mexico, from November 1998 to June 2016, were retrospectively analyzed.
RESULTS: The median age at transplantation was 23 (15 - 39) years. Most patients (n = 18, 62%) had testicular primary tumor, and 23 had metastases (79%). Complete response after auto - HSCT was observed in 45%. Non - relapse mortality was 0. Five - year relapse / progression free and overall survival were 67% and 69%, respectively.
CONCLUSIONS: This small single limited - resource institution study demonstrated that patients with poor - risk NSGCT are curable by first - line HDC plus autologous HSCT and that this procedure is feasible and affordable to perform using non - cryopreserved hematopoietic stem cells.

Kanno T, Matsui H, Akizawa Y, et al.
Treatment results of the second-line chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia treated with 5-day methotrexate and 5-day etoposide.
J Gynecol Oncol. 2018; 29(6):e89 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Highly effective chemotherapy for patients with low-risk gestational trophoblastic neoplasia (GTN) is associated with almost a 100% cure rate. However, 20%-30% of patients treated with chemotherapy need to change their regimens due to severe adverse events (SAEs) or drug resistance. We examined the treatment outcomes of second-line chemotherapy for patients with low-risk GTN.
METHODS: Between 1980 and 2015, 281 patients with low-risk GTN were treated. Of these 281 patients, 178 patients were primarily treated with 5-day intramuscular methotrexate (MTX; n=114) or 5-day drip infusion etoposide (ETP; n=64). We examined the remission rates, the drug change rates, and the outcomes of second-line chemotherapy.
RESULTS: The primary remission rates and drug resistant rates of 5-day ETP were significantly higher (p<0.001) and significantly lower (p=0.002) than those of 5-day MTX, respectively. Forty-seven patients (26.4%) required a change in their chemotherapy regimen due to the SAEs (n=16) and drug resistance (n=31), respectively. Of these 47 patients failed the first-line regimen, 39 patients (39/47, 82.9%) were re-treated with single-agent chemotherapy, and 35 patients (35/39, 89.7%) achieved remission. Four patients failed second-line, single-agent chemotherapy and eight patients (17.0%) who failed first-line regimens were treated with combined or multi-agent chemotherapy and achieved remission.
CONCLUSIONS: Patients with low-risk GTN were usually treated with single-agent chemotherapy, while 20%-30% patients had to change their chemotherapy regimen due to SAEs or drug resistance. The second-line regimens of single-agent chemotherapy were effective; however, there were several patients who needed multiple agents and combined chemotherapy to achieve remission.

Onec B, Okutan H, Albayrak M, et al.
Combination therapy with azacitidine, etoposide, and cytarabine in the treatment of elderly acute myeloid leukemia patients: A single center experience.
J Cancer Res Ther. 2018 Jul-Sep; 14(5):1105-1111 [PubMed] Related Publications
Aims: The prognosis of acute myeloid leukemia (AML) in elderly patients is worse due to age and comorbidities. Lately, monotherapy with hypomethylating agents like azacitidine (Aza) has been used to prolong overall survival (OS) in AML patients. Herein, we present a retrospective study investigating treatment responses and OS of Aza in combination with etoposide (Eto) and cytarabine (ARA-C) in elderly.
Materials and Methods: In this study, therapies and outcomes of 37 newly diagnosed AML patients, >60 years old, and ineligible for intensive chemotherapy were investigated retrospectively. Patients were grouped according to the treatments they received as follows - Group 1: low-dose conventional therapies as hydroxyurea, low-dose ARA-C, or best supportive care (n = 11); Group 2: Aza alone (n = 6); Group 3: Aza in combination with Eto and ARA-C (Aza + Eto + ARA-C, n = 20).
Results: It was found that an Aza + Eto + ARA-C combination therapy had significantly better overall response rates (P = 0.002). Combination group had significantly better OS than Group 1 (8 months vs. 1 month, P < 0.001), the difference between combination and monotherapy was not significant. The OS was also associated with age and performance status, but the difference was still statistically significant after adjustment for these factors, especially for patients with younger age and better performance.
Conclusions: We concluded that combination therapy of Aza with Eto and ARA-C increases response rates, and prolong survival for this poor prognosed patient group. We believe that larger controlled studies investigating Aza combinations with other antileukemic drugs will contribute to the development of tolerable treatment protocols for elderly AML patients.

Sverchinsky DV, Nikotina AD, Komarova EY, et al.
Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
The Hsp70 chaperone binds and inhibits proteins implicated in apoptotic signaling including Caspase-3. Induction of apoptosis is an important mechanism of anti-cancer drugs, therefore Hsp70 can act as a protective system in tumor cells against therapeutic agents. In this study we present an assessment of candidate compounds that are able to dissociate the complex of Hsp70 with Caspase-3, and thus sensitize cells to drug-induced apoptosis. Using the PASS program for prediction of biological activity we selected a derivative of benzodioxol (BT44) that is known to affect molecular chaperones and caspases. Drug affinity responsive target stability and microscale thermophoresis assays indicated that BT44 bound to Hsp70 and reduced the chaperone activity. When etoposide was administered, heat shock accompanied with an accumulation of Hsp70 led to an inhibition of etoposide-induced apoptosis. The number of apoptotic cells increased following BT44 administration, and forced Caspase-3 processing. Competitive protein⁻protein interaction and immunoprecipitation assays showed that BT44 caused dissociation of the Hsp70⁻Caspase-3 complex, thus augmenting the anti-tumor activity of etoposide and highlighting the potential role of molecular separators in cancer therapy.

Lan CY, Wang Y, Xiong Y, et al.
Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study.
Lancet Oncol. 2018; 19(9):1239-1246 [PubMed] Related Publications
BACKGROUND: Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer.
METHODS: In this phase 2, single-arm, prospective study, we recruited patients aged 18-70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956.
FINDINGS: Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6-71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2-78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded.
INTERPRETATION: The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted.

Abdel-Rahman O
Impact of baseline characteristics on extensive-stage SCLC patients treated with etoposide/carboplatin: A secondary analysis of a phase III study.
Clin Respir J. 2018; 12(10):2519-2524 [PubMed] Related Publications
BACKGROUND: The purpose of the current study is to investigate the impact of baseline characteristics on the outcomes of extensive-stage small cell lung cancer (SCLC) patients recruited into a clinical trial.
METHODS: This is a secondary analysis of the control arm (etoposide/carboplatin arm) of the 'NCT00363415' study which is a phase III study conducted between 2006 and 2007. Univariate analysis of factors affecting overall and progression-free survival (PFS) was conducted through Cox regression analysis [including age, race, gender, Eastern Cooperative Oncology Group performance score, body mass index, Lactate dehydrogenase, number of metastatic sites and brain metastases]. Factors with P < .05 in the univariate analysis were then included in the multivariate analysis.
RESULTS: All patients within the control arm (etoposide/carboplatin) were included in the analysis (N = 455 patients). The following factors were predictive of worse overall survival (OS) in univariate analysis (P < .05): performance score = 2, LDH > upper limit of normal and ≥3 metastatic sites. Multivariate Cox regression analysis incorporating these three factors showed that only number of metastatic sites predicts worse OS (P < .0001). Likewise, the following factors were associated with worse PFS in univariate analysis (P < .05): performance score = 2 and ≥ 3 metastatic sites predict worse PFS (P < .05). Multivariate analysis incorporating these two factors showed that only number of metastatic sites predicts worse PFS (P < .0001).
CONCLUSION: Number of metastatic sites is the most important predictive factor for overall and PFS among patients with extensive-stage SCLC treated with systemic chemotherapy within a clinical trial.

Laber DA, Chen MB, Jaglal M, et al.
Phase 2 Study of Cyclophosphamide, Etoposide, and Estramustine in Patients With Castration-Resistant Prostate Cancer.
Clin Genitourin Cancer. 2018; 16(6):473-481 [PubMed] Related Publications
BACKGROUND: There are no effective chemotherapies for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease has failed to respond to taxanes or patients who do not wish to receive intravenous drugs. We hypothesized that low doses of multiple medications with prolonged exposure would result in a high response rate and low toxicity.
PATIENTS AND METHODS: Patients with mCRPC were eligible for this phase 2 trial. The primary endpoint was a prostate-specific antigen decrease of more than 50%. CEE consisted of cyclophosphamide (50 mg/m
RESULTS: Fifty-two patients were enrolled and included in all evaluations. The prostate-specific antigen response rate was 46% in all patients, 53% in chemotherapy-naive subjects, and 31% after docetaxel chemotherapy. Thirty subjects had measurable lesions, 1 (3%) had complete response, 2 (7%) partial response, and 22 (73%) stable disease, for a clinical benefit of 83%. Sixty percent experienced an improvement in their performance status, and 65% reported improvement in their pain. The median overall survival was 18.6 months in all patients, 20.4 months in chemotherapy-naive patients and 11.3 months in patients whose disease progressed while receiving docetaxel therapy. Grade 3/4 treatment-related toxicities included 20% neutropenia, 10% thrombocytopenia, 10% deep-vein thrombosis, 8% anemia, 8% fatigue, 4% death, and 2% anorexia and stomatitis.
CONCLUSION: CEE was an all-oral, easy-to-administer, and effective triple-drug therapy for patients with mCRPC.

Wang Z, Liang P, He X, et al.
Etoposide loaded layered double hydroxide nanoparticles reversing chemoresistance and eradicating human glioma stem cells in vitro and in vivo.
Nanoscale. 2018; 10(27):13106-13121 [PubMed] Related Publications
Glioblastoma (GBM) is the most malignant and lethal glioma in human brain tumors and contains self-renewing, tumorigenic glioma stem cells (GSCs) that contribute to tumor initiation, therapeutic resistance and further recurrence. In this study, we combined in vitro cellular efficacy with in vivo antitumor performance to evaluate the outcome of an etoposide (VP16) loaded layered double hydroxide (LDH) nanocomposite (L-V) on human GSCs. The effects on GSC proliferation and apoptosis showed that loading with LDH could significantly sensitize GSCs to VP16 and enhance the GSC elimination. Further qPCR and western blot assays demonstrated that L-V could effectively attenuate GSC related pluripotency gene expression and reduce the cancer stemness. An in vivo GSC xenograft mice model showed that L-V can overcome drug resistance, eradicate GSCs, sharply decrease the stemness and reverse the epithelial-mesenchymal transition (EMT). RNA-seq analysis elucidated that L-V plays a vital role by down-regulating the PI3K/AKt/mTOR expression and activating the Wnt/GSK3β/β-catenin signaling pathway, hence leading to GSC stemness loss and greatly enhancing the GSC targeting effect. Taken together, this study demonstrated the outstanding performance of L-V reversing the drug resistance of GSCs, thus providing a novel strategy for clinical translation application of nanomedicine in malignant glioma chemotherapy.

Sirachainan N, Pakakasama S, Anurathapan U, et al.
Outcome of newly diagnosed high risk medulloblastoma treated with carboplatin, vincristine, cyclophosphamide and etoposide.
J Clin Neurosci. 2018; 56:139-142 [PubMed] Related Publications
Medulloblastoma is the most common malignant brain tumor among children. Although molecular study has been included in the new classification, in developing countries with limited resources the previous Chang staging system is still used. Therefore, treatment with postoperative radiation and chemotherapy remains the standard treatment. One common complication after treatment is ototoxicity, mainly due to radiation and cisplatinum. We report a revised chemotherapy protocol, replacing cisplatinum with carboplatin in newly diagnosed medulloblastoma cases. All 23 patients in this study had high risk medulloblastoma. Mean (SD) age was 9.5 ± 3.1 years. The 5-year progression free survival (PFS), 5-year overall survival (OS), and 10-year OS were 41.8 ± 12.2%, 60.0 ± 11.2%, and 48.0 ± 14.0 respectively. Most patients had grade 3-4 hematologic toxicity. Twelve patients had hearing tests, with 11 patients having grade 0 and 1 patient having grade 1 according to the Brock criteria.

Chen JC, Ma PF, Lin YC, et al.
17-(Allylamino)-17-Demethoxygeldanamycin Enhances Etoposide-Induced Cytotoxicity via the Downregulation of Xeroderma Pigmentosum Complementation Group C Expression in Human Lung Squamous Cell Carcinoma Cells.
Pharmacology. 2018; 102(1-2):91-104 [PubMed] Related Publications
Etoposide (VP16) is a topoisomerase II inhibitor and has been used for the treatment of non-small cell lung cancer (NSCLC). Xeroderma pigmentosum complementation group C (XPC) protein is a DNA damage recognition factor in nucleotide excision repair and involved in regulating NSCLC cell proliferation and viability. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. In this study, we report whether Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) enhanced etoposide-induced cytotoxicity in NSCLC cells through modulating the XPC expression. We found that etoposide increased XPC expression in an AKT activation manner in 2 squamous cell carcinoma H1703 and H520 cells. Knockdown of XPC using siRNA or inactivation of AKT by pharmacological inhibitor PI3K inhibitor (LY294002) enhanced the cytotoxic effects of etoposide. In contrast, enforced expression of XPC cDNA or AKT-CA (a constitutively active form of AKT) reduced the cytotoxicity and cell growth inhibition of etoposide. Hsp90 inhibitor 17-AAG enhanced cytotoxicity and cell growth inhibition of etoposide in NSCLC cells, which were associated with the downregulation of XPC expression and inactivation of AKT. Our findings suggested that the Hsp90 inhibition induced XPC downregulation involved in enhancing the etoposide-induced cytotoxicity in H1703 and H520 cells.

Zhang M, Tang Y, Zhu Z, et al.
Paclitaxel and etoposide-loaded Poly (lactic-co-glycolic acid) microspheres fabricated by coaxial electrospraying for dual drug delivery.
J Biomater Sci Polym Ed. 2018; 29(16):1949-1963 [PubMed] Related Publications
In this study, we fabricated paclitaxel (PTX) and etoposide (ETP) loaded Poly (lactic-co-glycolic acid) (PLGA) microspheres with core-shell structures and particle sizes ranging from 1 to 4 µm by coaxial electrospraying. The microspheres were analyzed by scanning electron microscopy (SEM), transmission electron microscopy (TEM). The drug loading rate and entrapment efficiency of the microspheres were detected by high performance liquid chromatograph (HPLC). Moreover, the drug release profiles and degradation of drug-loaded PLGA microspheres in vitro were investigated, respectively. The distinct layered structure that existed in the manufactured core-shell microspheres can be observed by TEM. The in vitro release profiles indicated that the PLGA/PTX + ETP (PLGA/PE) microspheres exhibited the controlled release of two drugs in a sequential manner. Cell Counting Kit-8 was used to detect the toxic and side effects of the microspheres on bone tumor cells. PTX and ETP for combination drug therapy loaded microspheres had more cytotoxic effect on saos-2 osteosarcoma cells than the individual drugs. In conclusion, core-shell PLGA microspheres by electrospraying for combination drug therapy is promising for medicine applications, the PLGA/PE microspheres have some potential for osteosarcoma treatment.

Shi T, Jiang R, Yu J, et al.
Addition of intraperitoneal cisplatin and etoposide to first-line chemotherapy for advanced ovarian cancer: a randomised, phase 2 trial.
Br J Cancer. 2018; 119(1):12-18 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We assessed the efficacy of adding intraperitoneal (IP) chemotherapy to standard first-line intravenous (IV) chemotherapy in epithelial ovarian cancer (EOC) patients.
METHODS: Patients with stage IIIC-IV EOC who underwent optimal debulking surgery were randomly assigned to four cycles of weekly IP chemotherapy with cisplatin (50 mg/m
RESULTS: Between 4/2009 and 9/2015, 218 patients were randomised, of whom 215 initiated treatment. In the IP/IV arm, 90.6% of patients completed 4 cycles of IP chemotherapy. The 12-month NPRs were 81.9% and 64.2% in the IP/IV and IV groups, respectively (HR 0.48 (95% CI 0.27-0.82)). The median progression-free survival (PFS) was increased in the IP/IV arm compared with that in the IV arm (22.4 vs. 16.8 months; HR 0.66 (0.48-0.91)) and in a subgroup with no gross cytoreduction (31.1 vs. 16.8 months; HR 0.46 (0.26-0.82)). Similar findings were detected with regard to time to first subsequent anticancer therapy (TFST) (25.9 vs. 18.0 months; P = 0.009) and time to second subsequent anticancer therapy (TSST) (40.8 vs. 30.1 months; P = 0.042). Grade 3/4 leukopenia, anaemia and gastrointestinal events were more common in the IP/IV arm, but the treatment burden was considered acceptable.
CONCLUSIONS: IP chemotherapy prior to IV chemotherapy was associated with an increased 12-month NPR and a longer TSST than IV alone in patients with EOC, albeit with acceptable toxic effects. Long-term follow-up is warranted to identify the effects of IP therapy on overall survival.

Igawa S, Shirasawa M, Ozawa T, et al.
Comparison of carboplatin plus etoposide with amrubicin monotherapy for extensive-disease small cell lung cancer in the elderly and patients with poor performance status.
Thorac Cancer. 2018; 9(8):967-973 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Carboplatin plus etoposide (CE) is a standard treatment for elderly patients with extensive-disease small cell lung cancer (ED-SCLC). However, amrubicin monotherapy (AMR) may be a feasible alternative. We compared the efficacies and safety profiles of CE and AMR for ED-SCLC in elderly patients and chemotherapy-naive patients with poor performance status (PS).
METHODS: The records of SCLC patients who received CE or AMR as first-line chemotherapy were retrospectively reviewed and their treatment outcomes evaluated.
RESULTS: Eighty-four patients (median age 72 years; 42 each received CR and AMR) were analyzed; 34 patients had a PS score of 2. There were no significant differences in patient characteristics between the treatment groups. The median progression-free survival rates of patients in the CE and AMR groups were 5.8 and 4.8 months, respectively (P = 0.04); overall survival was 14.0 and 8.5 months, respectively (P = 0.089). Twenty-three CE group patients received AMR as second-line chemotherapy; their median overall survival from first-line chemotherapy was 18.5 months. Grade 3 or higher neutropenia occurred more frequently in patients treated with AMR (64% vs. 40%; P = 0.02), as did febrile neutropenia (14% vs. 7%).
CONCLUSIONS: CE remains a suitable first-line treatment for ED-SCLC in elderly patients or those with poor PS in comparison with AMR.

Babincová M, Vrbovská H, Sourivong P, et al.
Application of Albumin-embedded Magnetic Nanoheaters for Release of Etoposide in Integrated Chemotherapy and Hyperthermia of U87-MG Glioma Cells.
Anticancer Res. 2018; 38(5):2683-2690 [PubMed] Related Publications
BACKGROUND/AIM: Malignant gliomas remain refractory to several therapeutic approaches and the requirement for novel treatment modalities is critical to combat this disease. Etoposide is a topoisomerase-II inhibitor, which promotes DNA damage and apoptosis of cancer cells. In this study, we prepared albumin with embedded magnetic nanoparticles and etoposide for in vitro evaluation of combined hyperthermia and chemotherapy.
MATERIAL AND METHODS: Magnetic nanoparticles were prepared by a modified co-precipitation method in the presence of human serum albumin and etoposide. A cellular proliferation assay was used to determine the effects of these nanostructures on the viability of U87 glioma cells in an alternating magnetic field.
RESULTS: The in vitro experiments showed that cell viability decreased to 59.4% after heat treatment alone and to 53.8% on that with free etoposide, while combined treatment resulted in 7.8% cell viability.
CONCLUSION: Integrating hyperthermia and chemotherapy using albumin co-embedded magnetic nanoheaters and etoposide may represent a promising therapeutic option for glioblastoma.

Choi KH, Kim JY, Lee DS, et al.
Clinical impact of boost irradiation to pelvic lymph node in uterine cervical cancer treated with definitive chemoradiotherapy.
Medicine (Baltimore). 2018; 97(16):e0517 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to analyze tumor control and clinical outcomes of patients with uterine cervical cancer treated by chemoradiotherapy according to pelvic lymph node (PLN) positivity and boost irradiation to PLN and to determine toxicities associated with boost irradiation.We retrospectively reviewed patients with uterine cervical cancer treated with chemoradiotherapy between March 2000 and April 2015. Clinical characteristics, failure pattern, and survival outcomes of patients with or without PLN metastasis and those with or without boost irradiation were analyzed.A total of 80 cases were PLN-negative and 46 were PLN-positive. A total of 11 patients underwent PLN boost irradiation. The 2-year and 5-year overall survival (OS) rates showed significant difference between the PLN-positive and PLN-negative groups (P = .010). The 2-year and 5-year progression-free survival (PFS) rates showed significant difference between the 2 groups (P = .032). The 2-year and 5-year OS rates of the no-boost irradiation group were 82.9% and 58.3%, respectively, whereas all patients in the boost irradiation group were alive at the time of analysis (P = .065). There was no recurrence in the boost irradiation group. The difference in PFS was significant between the boost and the no-boost irradiation groups (P = .023). The 2-year and 5-year pelvic-recurrence free survival (PRFS) did not show significant difference but the tendency of increased risk of pelvic recurrence in no-boost group (boost vs no-boost; 81.9% and 70.2% vs 100% and 100% in 2-year and 5-year PRFS, respectively, P = .156). Boost irradiation to PLN could improve locoregional control especially in large pelvic LN (≥1.5 cm). Our results showed that only 1 acute and late toxicity of higher than grade 3 occurred.PLN metastasis was significant prognostic factor in cervix cancer treated by chemoradiotherapy. In the boost irradiation group, there was no recurrence or death with significantly better PFS. Boost irradiation to PLN is expected to improve locoregional control, but further follow-up and assessment are needed.

Grohmann T, Penke M, Petzold-Quinque S, et al.
Inhibition of NAMPT sensitizes MOLT4 leukemia cells for etoposide treatment through the SIRT2-p53 pathway.
Leuk Res. 2018; 69:39-46 [PubMed] Related Publications
NAMPT (Nicotinamide phosphoribosyltransferase) catalyses the rate-limiting step in the NAD biosynthesis from nicotinamide and thereby regulates the activity of NAD-dependent enzymes. Cancer cells are highly dependent on NAD for energy and DNA repair processes and are assumed to be more susceptible to an inhibition of NAD synthesis than non-transformed cells. We aimed to investigate whether or not inhibition of NAMPT with its specific inhibitor FK866 can sensitize leukemia cells for chemotherapeutic agents. NAMPT protein abundance, enzymatic activity and NAD concentrations were significantly higher in Jurkat and Molt-4 leukemia cell lines compared to normal peripheral blood mononuclear cells. Combination of etoposide and FK866 caused increased cell death in leukemia cell lines compared to etoposide alone. Etoposide decreased protein abundance of NAD-dependent deacetylases SIRTUIN1. After combining etoposide and FK866 treatment SIRTUIN2 was further decreased and accumulation and acetylation of the downstream target p53 was further enhanced in MOLT4 cells. Concomitantly, protein abundance of p21 and cleaved BAX was increased. Targeting NAMPT could be a novel therapeutic strategy to enhance the efficacy of chemotherapeutic agents such as etoposide against leukemia.

Takayoshi K, Doi G, Tsuruta N, et al.
Successful chemotherapeutic treatment for metastatic littoral cell angioma: A case report.
Medicine (Baltimore). 2018; 97(15):e0378 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Metastatic littoral cell angioma (LCA) is extremely rare. No standard therapeutic strategy has been established, and the impact of chemotherapy has not yet been evaluated.
PATIENT CONCERNS: A 61-year-old woman was admitted because of bicytopenia. She had a splenectomy for LCA of the spleen 10 years earlier. Bone marrow aspiration was normal, and a computed tomography (CT) scan showed hepatomegaly with multiple liver tumors.
DIAGNOSES: Liver biopsy samples showed macrophage-like cell infiltration in the hepatic sinusoids. Metastatic LCA was diagnosed based on immunohistochemistry, imaging tests, and the clinical course.
INTERVENTIONS: Immunosuppressive agents, such as prednisolone and cyclosporine, were ineffective. Next, cytotoxic agents, such as etoposide, paclitaxel, and vincristine, were administered.
OUTCOMES: Cytotoxic agents showed a prominent effect against LCA. CT showed improvement of the hepatomegaly, and fluoro-deoxyglucose (FDG) uptake decreased markedly at a follow-up FDG- positron emission tomography (PET) scan.
LESSONS: Chemotherapeutic treatment based on hemophagocytic syndrome or angiosarcoma might have anti-tumor activity against metastatic LCA. Analysis of the molecular characteristics of this tumor is needed to develop better treatment options.

Czyz A, Labopin M, Giebel S, et al.
Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph-negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: On behalf of the ALWP of the European Society for Blood and Marrow Transplantation.
Am J Hematol. 2018; 93(6):778-785 [PubMed] Related Publications
Allogeneic hematopoietic cell transplantation (alloHCT) with myeloablative conditioning based on total body irradiation (TBI) is widely used for the treatment of adults with acute lymphoblastic leukemia (ALL). TBI is most frequently administered in combination with either cyclophosphamide (Cy/TBI) or etoposide (Vp/TBI). The goal of this study was to retrospectively compare these two regimens. Adult patients with Ph-negative ALL treated with alloHCT in first or second complete remission who received Cy/TBI (n = 1346) or Vp/TBI (n = 152) conditioning were included in the analysis. In a univariate analysis, as compared to Cy/TBI, the use of Vp/TBI was associated with reduced incidence of relapse (17% vs. 30% at 5 years, P = .007), increased rate of leukemia-free survival (60% vs. 50%, P = .04), and improved "graft versus host disease (GVHD) and relapse-free survival" (GRFS, 43% vs. 33%, P = .04). No significant effect could be observed in terms of the incidence of nonrelapse mortality or acute or chronic GVHD. In a multivariate model, the use of Vp/TBI was associated with reduced risk of relapse (HR = 0.62, P = .04) while the effect on other study end-points was not significant. In conclusion, conditioning regimen based on Vp combined with TBI appears more effective for disease control than the combination of Cy with TBI for adult patients with Ph-negative ALL treated with alloHCT.

Wan X, Min Y, Bludau H, et al.
Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer.
ACS Nano. 2018; 12(3):2426-2439 [PubMed] Free Access to Full Article Related Publications
Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline- block-2-butyl-2-oxazoline- block-2-methyl-2-oxazoline) (P(MeOx- b-BuOx- b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

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