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Etoposide

"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

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

Moon JY, Baek SW, Ryu H, et al.
VIP (etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma.
Medicine (Baltimore). 2017; 96(4):e5942 [PubMed] Free Access to Full Article Related Publications
We retrospectively reviewed outcomes of treatment with VIP (combination of etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma (STS).We analyzed the medical records of patients with advanced or relapsed STS who had undergone VIP treatment as second-line or more chemotherapy between January 2000 and December 2015. The patients were treated with a combination of etoposide (100 mg/m for 5 days), ifosfamide (2000 mg/m for 2 days), and cisplatin (20 mg/m for 5 days) once every 4 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and nonresponder groups (responders showed a tumor response to any prior systemic chemotherapy before VIP).Twenty-four patients with a median age of 50 years (range: 20-68 years) were treated with VIP. Eleven (45.8%) patients were male and 7 (29.2%) received 2 or more chemotherapy regimens before VIP. Median PFS was 3.7 months (95% confidence interval [CI], 1.3-6.1 months) and median OS was 10.0 months (95% CI, 6.6-13.5). The overall response rate was 37.5%, and the disease control rate was 50%. The responder group showed better PFS (7.7 months vs 3.0 months; P = 0.101) and significantly improved OS (11.0 months vs 8.8 months; P = 0.039) compared to those of nonresponders. All patients reported some grade of hematological toxicity. The most frequently encountered hematological toxicity was neutropenia (any grade, 77.7%; grade 3 or 4, 74.0%).VIP might be effective in patients with previously treated STS.

Jiang H, Geng D, Liu H, et al.
Co-delivery of etoposide and curcumin by lipid nanoparticulate drug delivery system for the treatment of gastric tumors.
Drug Deliv. 2016; 23(9):3665-3673 [PubMed] Related Publications
CONTEXT: Gastric carcinoma (GC) is one of the most common cancers and the second most frequent cause of cancer-related deaths. Chemotherapy is an important therapeutic modality for GC. However, chemoresistance limited its success rate. Combination chemotherapy is often applied to prevent drug-induced resistance in cancers.
OBJECTIVE: The aim of this study is to evaluate whether the co-delivery of etoposide (ETP) and curcumin (CUR) with one nanoparticle can result in synergistic effects of both drugs.
METHODS: ETP- and CUR-loaded nanostructured lipid carriers (ETP-CUR-NLC) were prepared by the solvent injection technique. Their average size, zeta potential and drug loading were evaluated. Human gastric cancer cell lines (SGC7901 cells) were used for the testing of in vitro cytotoxicity studies, and in vivo anti-tumor efficacies of the carriers were evaluated on mice bearing SGC7901 cells xenografts.
RESULTS: ETP-CUR-NLC has a particle size of 114 nm, EPT-loading quantity of 83% and CUR-loading quantity of 82%. ETP-CUR-NLC displayed high cytotoxicity and enhanced antitumor activity in vitro and in vivo. Meanwhile, ETP-CUR-NLC displayed low cytotoxicity in normal tissues in vivo.
DISCUSSION AND CONCLUSION: The results demonstrate that ETP-CUR-NLC can achieve impressive anti-tumor activity. By combining CUR, an effective NF-κB inhibitor, with ETP, a powerful anticancer drug, in NLC, we could improve the therapeutic efficacy in cancer treatments. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against various malignancies.

Liu MY, Wang WZ, Liao FF, et al.
Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro.
Cell Biol Int. 2017; 41(1):16-23 [PubMed] Related Publications
Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) patient survival markedly but fail to eradicate quiescent CML leukemia stem cells (LSCs). Thus, strategies targeting LSCs are required to induce long-term remission and achieve cure. Here, we investigated the ability of topoisomerase II (Top II) inhibitor etoposide (Eto) to target CML LSCs. Treatment with Eto combined with IM markedly induced apoptosis in primitive CML CD34(+) CD38(-) stem cells resistant to eradication by IM alone, but not in normal hematopoietic stem cells, CML and normal mature CD34(-) cells, and other leukemia and lymphoma cell lines. The interaction of IM and Eto significantly inhibited phosphorylation of PDK1, AKT, GSK3, S6, and ERK proteins; increased the expression of pro-apoptotic gene Bax; and decreased the expression of anti-apoptotic gene c-Myc in CML CD34(+) cells. Top II inhibitors treatment represents an attractive approach for targeting LSCs in CML patients undergoing TKIs monotherapy.

Jafarlou M, Baradaran B, Shanehbandi D, et al.
siRNA-mediated inhibition of survivin gene enhances the anti-cancer effect of etoposide in U-937 acute myeloid leukemia cells.
Cell Mol Biol (Noisy-le-grand). 2016; 62(6):44-9 [PubMed] Related Publications
Acute myeloid leukemia (AML) is one of the most frequent types of leukemia which mostly affects adult people. Resistance to therapeutic drugs is considered as a major clinical concern resulting in a weaker response to chemotherapy, disease relapse and decreased survival rate. Survivin, a member of Inhibitor of Apoptosis Proteins (IAPs), is associated with drug resistance and inhibition of apoptotic mechanisms in numerous hematological malignancies. In the present study, we examined the combined effect of etoposide and siRNA-mediated silencing of survivin on U-937 acute myeloid leukemia cells. The AML cells were transfected with survivin specific siRNA and gene knockdown was confirmed by quantitative real time PCR and western blotting. Subsequently, U-937 cells were assessed for response to etoposide treatment and apoptosis rate was measured with flowcytometery. The cytotoxic effects in siRNA-etoposide group were measured and compared to etoposide single therapy group. Survivin siRNA effectively knocked down the mRNA and protein levels of survivin, which led to lower cell proliferation and enhanced apoptosis. Furthermore, combined treatment of etoposide and survivin siRNA synergistically increased the cell toxic effects of etoposide and its ability to induce apoptosis.

Yang H, Yao J, Yin J, Wei X
Decreased LRIG1 in Human Ovarian Cancer Cell SKOV3 Upregulates MRP-1 and Contributes to the Chemoresistance of VP16.
Cancer Biother Radiopharm. 2016; 31(4):125-32 [PubMed] Related Publications
The leucine-rich repeats and immunoglobulin-like domains (LRIG) are used as tumor suppressors in clinical applications. Although the LRIG has been identified to manipulate the cell proliferation via various oncogenic receptor tyrosine kinases in diverse cancers, its role in multidrug resistance needs to be further elucidated, especially in human ovarian cancer. We herein established that the etoposide (VP16)-resistant SKOV3 human ovarian cancer cell clones (SKOV3/VP16 cells) and mRNA expression of LRIG1 were significantly reduced by the treatment of VP16 in a concentration-dependent manner. Moreover, downregulated LRIG1 in SKOV3 could enhance the colony formation and resist the inhibition of proliferation by VP16, leading to the elevated expression of Bcl-2 and decreased apoptosis of SKOV3. Interestingly, our results uncovered that the multidrug resistance-associated protein 1 (MRP-1) was upregulated for the chemoresistance of VP16. To overcome the chemoresistance of SKOV3, SKOV3/VP16 was ectopically expressed of LRIG1. We found that the inhibition of VP16 on colony formation and proliferation was remarkably enhanced with increased apoptosis in SKOV3/VP16. Furthermore, the expression of MRP-1 and Bcl-2 was also inhibited, suggesting that the LRIG1could negatively control MRP-1 and the apoptosis to improve the sensitivity of VP16-related chemotherapy.

Kumar A, Ehrenshaft M, Tokar EJ, et al.
Nitric oxide inhibits topoisomerase II activity and induces resistance to topoisomerase II-poisons in human tumor cells.
Biochim Biophys Acta. 2016; 1860(7):1519-27 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: Etoposide and doxorubicin, topoisomerase II poisons, are important drugs for the treatment of tumors in the clinic. Topoisomerases contain several free sulfhydryl groups which are important for their activity and are also potential targets for nitric oxide (NO)-induced nitrosation. NO, a physiological signaling molecule nitrosates many cellular proteins, causing altered protein and cellular functions.
METHODS: Here, we have evaluated the roles of NO/NO-derived species in the activity/stability of topo II both in vitro and in human tumor cells, and in the cytotoxicity of topo II-poisons, etoposide and doxorubicin.
RESULTS: Treatment of purified topo IIα with propylamine propylamine nonoate (PPNO), an NO donor, resulted in inhibition of both the catalytic and relaxation activity in vitro, and decreased etoposide-dependent cleavable complex formation in both human HT-29 colon and MCF-7 breast cancer cells. PPNO treatment also induced significant nitrosation of topo IIα protein in these human tumor cells. These events, taken together, caused a significant resistance to etoposide in both cell lines. However, PPNO had no effect on doxorubicin-induced cleavable complex formation, or doxorubicin cytotoxicity in these cell lines.
CONCLUSION: Inhibition of topo II function by NO/NO-derived species induces significant resistance to etoposide, without affecting doxorubicin cytotoxicity in human tumor cells.
GENERAL SIGNIFICANCE: As tumors express inducible nitric oxide synthase and generate significant amounts of NO, modulation of topo II functions by NO/NO-derived species could render tumors resistant to certain topo II-poisons in the clinic.

Jia H, Yang Q, Wang T, et al.
Rhamnetin induces sensitization of hepatocellular carcinoma cells to a small molecular kinase inhibitor or chemotherapeutic agents.
Biochim Biophys Acta. 2016; 1860(7):1417-30 [PubMed] Related Publications
BACKGROUND: The rapid development of multi-drug resistance (MDR) process has hindered the effectiveness of advanced hepatocellular carcinoma (HCC) treatments. Notch-1 pathway, which mediates the stress-response, promotes cell survival, EMT (epithelial-mesenchymal transition) process and induces anti-apoptosis in cancer cells, would be a potential target for overcoming MDR process. This study investigated the potential application of rhamnetin, a specific inhibitor of Notch-1 pathway, in anti-tumor drug sensitization of HCC treatment.
METHODS: The expression of miR-34a, proteins belonging to Notch-1 signaling pathway or MDR-related proteins was detected by quantitative polymerase chain reaction (qPCR) and western blot assay. To identify whether rhamnetin induces the chemotherapeutic sensitization in HCC cells, the MTT-assays, flow cytometry, soft agar, trans-well and nude mice assays were performed.
RESULTS: The endogenous expression of miR-34a was significantly increased and the expression of Notch-1 and Survivin was downregulated after rhamnetin treatment. Treatment of rhamnetin also reduced the expression of MDR related proteins P-GP (P-glycoprotein) and BCRP (breast cancer resistance protein). Rhamnetin increased the susceptibility of HCC cells and especially HepG2/ADR, a MDR HCC cell line, to a small molecular kinase inhibitor sorafenib or chemotherapeutic drugs etoposide and paclitaxel. The IC(50) value of those drugs correspondingly decreased.
CONCLUSIONS: Together, our findings suggest that rhamnetin treatment may attenuate the MDR process in HCC cells. These findings may contribute to more effective strategies for HCC therapy.
GENERAL SIGNIFICANCE: Rhamnetin acts as a promising sensitizer to chemotherapy and may be a novel approach to overcome the MDR process of HCC.

Sun Y, Cheng Y, Hao X, et al.
Randomized phase III trial of amrubicin/cisplatin versus etoposide/cisplatin as first-line treatment for extensive small-cell lung cancer.
BMC Cancer. 2016; 16:265 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: Extensive-disease small-cell lung cancer (ED-SCLC) is characterized by rapid progression and relapse, despite high initial response rates to chemotherapy. The primary objective of this trial was to demonstrate the non-inferiority of amrubicin and cisplatin (AP) combination therapy compared with the standard first-line regimen of etoposide and cisplatin (EP) for previously untreated ED-SCLC in a Chinese population. When non-inferiority was verified, the objective was switched from non-inferiority to superiority.
METHODS: From June 2008 to July 2010, 300 patients were enrolled and randomly assigned at a 1:1 ratio to AP and EP groups. AP-treated patients received cisplatin (60 mg/m(2), day 1) and amrubicin (40 mg/m(2), days 1-3) once every 21 days. EP-treated patients received cisplatin (80 mg/m(2), day 1) and etoposide (100 mg/m(2), days 1-3) once every 21 days. Treatment was continued for four to six cycles, except in cases of progressive disease or toxicity, and patient refusal.
RESULTS: Median overall survival (OS) for AP vs. EP treatment was 11.8 vs. 10.3 months (p = 0.08), respectively, demonstrating non-inferiority of AP to EP (AP group: 95% confidence interval for hazard ratio 0.63-1.03 months). Median progression-free survival and overall response rates for AP vs. EP groups were 6.8 vs. 5.7 months (p = 0.35) and 69.8% vs. 57.3%, respectively. Drug-related adverse events in both groups were similar, with neutropenia being the most frequent (AP 54.4%; EP 44.0%). Leukopenia, pyrexia, and fatigue were more prevalent in the AP group, but all were clinically reversible and manageable.
CONCLUSIONS: AP therapy demonstrated non-inferiority to EP therapy, prolonging OS for 1.5 months, but this difference was not statistically significant; thus we propose AP as a promising treatment option for ED-SCLC in China.
TRIAL REGISTRATION: This trial was registered on 10 April 2008 (ClinicalTrials.gov NCT00660504).

Jafarlou M, Baradaran B, Shanehbandi D, et al.
Silencing of myeloid cell leukemia-1 by small interfering RNA improves chemosensitivity to etoposide in u-937 leukemic cells.
J Biol Regul Homeost Agents. 2016 Jan-Mar; 30(1):55-65 [PubMed] Related Publications
A key issue in the treatment of acute myeloid leukemia (AML) is the development of drug resistance to chemotherapeutic agents. Overexpression of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic protein, is associated with tumor progression and drug resistance in leukemia and several cancers. The purpose of this study was to investigate the effect of specific Mcl-1 small interference RNA (siRNA) on the proliferation and chemosensitivity of U-937 AML cell to etoposide. The siRNA transfection was conducted using Lipofectamine™ 2000. Quantitative real-time RT-PCR (qRT-PCR) and Western blot analysis were employed to measure the expression levels of mRNA and protein, respectively. To evaluate tumor cell growth after siRNA transfection, Trypan blue exclusion assay was conducted. The cytotoxic effects of siRNA and etoposide were determined using MTT assay on their own and in combination. DNA-histone ELISA and annexin-V/FITC assays were performed to study the apoptosis. Mcl-1 siRNA transfection significantly blocked the expression of Mcl-1 mRNA and protein in a time-dependent manner, leading to a strong growth inhibition and enhanced apoptosis (P less than 0.05). Furthermore, pretreatment with Mcl-1 siRNA, synergistically enhanced the cytotoxic and apoptotic effects of etoposide (P less than 0.05). Our results demonstrated that Mcl-1 plays a fundamental role in the survival and resistance of U-937 cells to etoposide. Therefore, Mcl-1 can be considered an attractive target in gene therapy of AML patients and siRNA-mediated silencing of this gene may be a novel strategy in AML treatment.

Paul D, Chanukuppa V, Reddy PJ, et al.
Global proteomic profiling identifies etoposide chemoresistance markers in non-small cell lung carcinoma.
J Proteomics. 2016; 138:95-105 [PubMed] Related Publications
UNLABELLED: Chemoresistance is one of the leading health concerns in cancer treatment. Understanding the mechanism of chemoresistance is the best way to improve the survival of the patient. Etoposide and its analogues are widely used as antitumor drugs in lung cancer but many etoposide resistant lung cancer cases has been identified in recent years. The present study aims to explore the cellular response of lung cancer cell lines to etoposide and finding the potential chemoresistant marker proteins. Multiple proteomic platforms like 2-DE, DIGE and iTRAQ have been used to study the global proteome profile of NCI-H460 and etoposide resistant NCI-H460R cell lines. Our study revealed that etoposide treatment leads to alteration of 83 proteins in NCI-H460R cell lines. The functional analysis highlighted the role of the differential expressed proteins in cellular signaling, apoptosis, and cytoskeleton reorganization. Our study has identified several new proteins like RHOC, DLG5, UGDH, TMOD3 in addition to known chemoresistance associated proteins. In silico prediction of the important selected candidates are further validated at protein and mRNA level. Further, functional studies of newly identified candidate genes RHOC and DLG5 revealed that chemotherapeutic resistance is associated with their elevated level and may serve as novel targets for therapeutic intervention.
BIOLOGICAL SIGNIFICANCE: Etoposide and its analogues have been used for lung cancer treatment for a while and it was reported that many non small cell lung carcinoma patients are resistant to etoposide. Although etoposide show drug resistance, the exact mechanism was not well understood. The present study focused on the global proteome analysis of NCI-H460 and NCI-H460R cell lines using multiple proteomic platforms to understand the potential chemoresistant markers for etoposide. Our multi-proteomic analysis has showed differential expression of 83 proteins involved in oxidative phosphorylation, metabolic, protein folding, cytoskeleton associated protein along with apoptotic pathway has been identified. In addition, quite a few interesting proteins such as RHOC, DLG5, HSP90, citrate synthase, UDP-glucose-6-dehydrogenase, Tropomodulin-3 are involved in chemoresistance has been observed. Overall, this is the first comprehensive proteomic study on etoposide resistant cell line NCI-H460 to explore the mechanism of chemoresistance in lung cancer.

Papież MA, Krzyściak W, Szade K, et al.
Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species.
Drug Des Devel Ther. 2016; 10:557-70 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34(+) cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34(+) cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.

Kimura K, Huang RC
Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01.
PLoS One. 2016; 11(2):e0148685 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines. In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP, AsPC-1, and L428 cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments.

Podda MG, Luksch R, Puma N, et al.
Oral etoposide in relapsed or refractory Ewing sarcoma: a monoinstitutional experience in children and adolescents.
Tumori. 2016 Jan-Feb; 102(1):84-8 [PubMed] Related Publications
AIMS: To assess the efficacy and toxicity of low-dose oral etoposide (VP) 16 in relapsing/refractory Ewing sarcoma.
METHODS: The records of all patients treated at our department between 1989 and 2012 for relapsing/refractory Ewing sarcoma who received oral VP-16 were analyzed. The dose was 40 mg/m2 daily for 21 consecutive days in every 28. Response was assessed after 2/3 cycles according to Response Evaluation Criteria in Solid Tumors 1.0.
RESULTS: A total of 46 of 58 patients completed at least 2 cycles; 12 suspended the treatment earlier due to rapid disease progression. The patients' median age at diagnosis was 14 years and 25/58 had metastatic disease. All patients received intensive polychemotherapy including VP-16 IV as first- (n = 53) or second-line (n = 5) treatment; 21/58 had myeloablative regimens with peripheral blood stem cell rescue, and 1 underwent allogeneic stem cell transplantation. Oral VP-16 was prescribed as 2nd-, 3rd-, and 4th-line treatment for 19, 27, and 12 patients, respectively. The cycles administered totaled 241 (median 3, mean 4 per patient; range 1-14). A total of 46 of 58 patients were evaluable: 11 responded (9 partial remission, 1 very good partial remission, 1 complete remission) and 10 were stable, the response lasting a mean of 8 months. Hematologic toxicity G3/G4 (in 164/241 evaluable cycles) occurred in 15%, 16%, and 11% of cycles for leukocytes, hemoglobin, and platelets, respectively. There were 5 cases of pneumonia. Two patients developed secondary leukemia after receiving 12 and 14 cycles.
CONCLUSIONS: Low-dose oral VP-16 may be suitable in a palliative setting with an acceptable toxicity. The risk of secondary leukemia is in line with reports in the literature.

Kuo YC, Lee CH
Dual targeting of solid lipid nanoparticles grafted with 83-14 MAb and anti-EGF receptor for malignant brain tumor therapy.
Life Sci. 2016; 146:222-31 [PubMed] Related Publications
AIMS: Solid lipid nanoparticles (SLNs) conjugated with surface 83-14 monoclonal antibody (8314MAb) and anti-epithelial growth factor receptor (AEGFR) were synthesized and applied to permeate the blood-brain barrier (BBB) and inhibit the growth of glioblastoma multiforme (GBM).
MAIN METHODS: 8314MAb and AEGFR were crosslinked on SLNs to carry etoposide (ETP) across human brain-microvascular endothelial cells (HBMECs) and to treat U87MG cells.
KEY FINDINGS: An increase in the 8314MAb concentration increased the permeability for propidium iodide (PI) and ETP across the BBB, however, decreased the 8314MAb grafting efficiency and transendothelial electrical resistance of the monolayer of HBMECs. In addition, an increase in the AEGFR concentration enhanced the viability of HBMECs and human astrocytes (HAs), however, reduced the AEGFR grafting efficiency and ETP release rate. An incorporation of both 8314MAb and AEGFR increased the particle size, however, decreased the zeta potential, ETP release rate, and viability of HBMECs and HAs.
SIGNIFICANCE: The conjugation of 8314MAb and AEGFR on ETP-loaded SLNs can be a promising strategy to deliver antitumor ETP to the brain and restrain the propagation of GBM.

Khattry N, Gupta A, Jain R, et al.
LACE versus BEAM conditioning in relapsed and refractory lymphoma transplant: retrospective multicenter analysis of toxicity and efficacy.
Int J Hematol. 2016; 103(3):292-8 [PubMed] Related Publications
We compared the lomustine, cytarabine, cyclophosphamide and etoposide (LACE) and BCNU, etoposide, cytarabine, melphalan (BEAM) conditioning regimens for toxicity, engraftment kinetics, and efficacy in 139 patients undergoing autologous hematopoietic stem cell transplant for primary refractory or relapsed lymphoma. Ninety-two patients with Hodgkin lymphoma and 47 with non-Hodgkin lymphoma were enrolled. Seventy-five patients received LACE while 64 received BEAM. The incidence of grade 3-4 oral mucositis (9 vs 38%; P < 0.001) and parenteral nutrition requirement (32 vs 69%; P < 0.001) were significantly lower in the LACE cohort. The median days to myeloid (10 vs 11; P = 0.007) and platelet engraftment (13 vs 15; P = 0.026) were shorter for the LACE cohort. Transplant-related mortality in the LACE group was 9% compared to 13% in patients treated with BEAM (P = NS). The probability of overall survival (OS) and progression-free survival (PFS) at 5 years for entire cohort was 46 and 41%, respectively. Probability of OS (LACE 46% vs BEAM 47%; P = NS) and PFS (LACE 37% vs BEAM 47%; P = NS) at 5 years was comparable between two groups. We conclude that LACE has better toxicity profile compared to BEAM and results in similar long-term survival in primary refractory or relapsed lymphoma transplant.

Elborai Y, Hafez H, Moussa EA, et al.
Comparison of toxicity following different conditioning regimens (busulfan/melphalan and carboplatin/etoposide/melphalan) for advanced stage neuroblastoma: Experience of two transplant centers.
Pediatr Transplant. 2016; 20(2):284-9 [PubMed] Related Publications
The outcome for advanced neuroblastoma has improved with combined modality therapy: induction chemotherapy, surgery, and consolidation with high-dose chemotherapy/autologous HSCT, followed by local radiation, cisretinoic acid, and recently antibody therapy. In the United States, the most common conditioning regimen is CEM, while in Europe/Middle East, Bu/Mel has been widely used; it remains unclear which regimen has the best outcome. Assess renal, hepatic, and infectious toxicity through Day+100 in 2 different regimens. Retrospective comparison between CEM-DFCHCC Boston and Bu/Mel- CCHE-57357. Thirty-five patients, median age 4, in Boston (2007-2011) and 38 patients, median age 3, in Cairo (2009-2011). Renal toxicity; creatinine was significantly higher in CEM than Bu/Mel: 57% (median day+90) vs. 29% (median>day+100), p = 0.004. One CEM patient died from renal dialysis at day+19. Hepatic toxicity was significantly higher in CEM than Bu/Mel: 80% (median day+26) vs. 58% (median day+60), p = 0.04. In infectious complications with CEM 14%, bacteremia (n = 4) and fungemia (n = 1), 3 had culture-negative sepsis requiring vasopressors. With Bu/Mel 18%, bacteremia (n = 7), none required pressors, p = 0.4. Bu/Mel was associated with less acute hepatic and renal toxicity and thus may be preferable for preserving organ functions.

Okada N, Watanabe H, Kagami S, Ishizawa K
Ifosfamide and etoposide chemotherapy may interact with warfarin, enhancing the warfarin induced anticoagulant response.
Int J Clin Pharmacol Ther. 2016; 54(1):58-61 [PubMed] Related Publications
PURPOSE: To report a case of warfarin-response enhancement during administration of ifosfamide and etoposide chemotherapy.
CASE SUMMARY: A 15-yearold boy with rhabdomyosarcoma was treated with a regimen of alternating cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) chemotherapy and ifosfamide and etoposide (IE) chemotherapy. During VDC chemotherapy, occlusion of the left middle cerebral artery occurred, and warfarin was started. On day 3 of IE chemotherapy, the patient's international normalized ratio (INR) transiently increased from baseline 2.61 to 5.45. The INR returned to normal within 3 days after warfarin discontinuation. An increase in INR was observed between days 1 and 3 of subsequent cycles of IE chemotherapy but not during VDC chemotherapy. This INR increase was also observed during concomitant use of aprepitant, an inducer of the CYP2C9.
DISCUSSION: There are no reports describing the interaction between warfarin and IE chemotherapy because coadministration of warfarin and IE chemotherapy is unusual. The Drug Interaction Probability Scale score of this interaction was 7, and it is probable that the enhancement of the warfarin response was caused by an interaction with IE chemotherapy. Moreover, in the present case, the enhancement of warfarin response was observed during concomitant use of aprepitant, which has been reported to weaken the warfarin response. Therefore, this interaction may be quite powerful and may increase the risk of warfarin toxicity.
CONCLUSION: A patient who was administered both warfarin and IE chemotherapy experienced a rapid increase in INR, suggesting that INR should be closely monitored in patients receiving warfarin with IE chemotherapy.

Srinivas C, Ramaiah MJ, Lavanya A, et al.
Novel Etoposide Analogue Modulates Expression of Angiogenesis Associated microRNAs and Regulates Cell Proliferation by Targeting STAT3 in Breast Cancer.
PLoS One. 2015; 10(11):e0142006 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

Su BH, Shieh GS, Tseng YL, et al.
Etoposide enhances antitumor efficacy of MDR1-driven oncolytic adenovirus through autoupregulation of the MDR1 promoter activity.
Oncotarget. 2015; 6(35):38308-26 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Conditionally replicating adenoviruses (CRAds), or oncolytic adenoviruses, such as E1B55K-deleted adenovirus, are attractive anticancer agents. However, the therapeutic efficacy of E1B55K-deleted adenovirus for refractory solid tumors has been limited. Environmental stress conditions may induce nuclear accumulation of YB-1, which occurs in multidrug-resistant and adenovirus-infected cancer cells. Overexpression and nuclear localization of YB-1 are associated with poor prognosis and tumor recurrence in various cancers. Nuclear YB-1 transactivates the multidrug resistance 1 (MDR1) genes through the Y-box. Here, we developed a novel E1B55K-deleted adenovirus driven by the MDR1 promoter, designed Ad5GS3. We tested the feasibility of using YB-1 to transcriptionally regulate Ad5GS3 replication in cancer cells and thereby to enhance antitumor efficacy. We evaluated synergistic antitumor effects of oncolytic virotherapy in combination with chemotherapy. Our results show that adenovirus E1A induced E2F-1 activity to augment YB-1 expression, which shut down host protein synthesis in cancer cells during adenovirus replication. In cancer cells infected with Ad5WS1, an E1B55K-deleted adenovirus driven by the E1 promoter, E1A enhanced YB-1 expression, and then further phosphorylated Akt, which, in turn, triggered nuclear translocation of YB-1. Ad5GS3 in combination with chemotherapeutic agents facilitated nuclear localization of YB-1 and, in turn, upregulated the MDR1 promoter activity and enhanced Ad5GS3 replication in cancer cells. Thus, E1A, YB-1, and the MDR1 promoter form a positive feedback loop to promote Ad5GS3 replication in cancer cells, and this regulation can be further augmented when chemotherapeutic agents are added. In the in vivo study, Ad5GS3 in combination with etoposide synergistically suppressed tumor growth and prolonged survival in NOD/SCID mice bearing human lung tumor xenografts. More importantly, Ad5GS3 exerted potent oncolytic activity against clinical advanced lung adenocarcinoma, which was associated with elevated levels of nuclear YB-1 and cytoplasmic MDR1 expression in the advanced tumors. Therefore, Ad5GS3 may have therapeutic potential for cancer treatment, especially in combination with chemotherapy. Because YB-1 is expressed in a broad spectrum of cancers, this oncolytic adenovirus may be broadly applicable.

Režonja Kukec R, Grabnar I, Mrhar A, et al.
A simple dried blood spot method for clinical pharmacological analyses of etoposide in cancer patients using liquid chromatography and fluorescence detection.
Clin Chim Acta. 2016; 452:99-105 [PubMed] Related Publications
BACKGROUND: Therapeutic drug monitoring of etoposide is not part of the routine clinical practice, however, measuring etoposide plasma concentration may be useful to prevent chemotherapy related adverse drug reactions. This paper describes the development and validation of a dried blood spot (DBS) assay for the determination of etoposide in blood samples of lung cancer patients.
METHODS: The whole blood spot was cut out of the DBS card followed by sonication assisted liquid drug extraction. Extraction solution was evaporated and re-dissolved. A high-performance-liquid-chromatography method with fluorimetric detection ( λex=230nm; λem=330nm) was used.
RESULTS: Method met the validation criteria in terms of selectivity, linearity (0.5-20.0μg/mL), accuracy (≥96.1%), precision (≤10.1%) and stability (long term 4weeks at room temperature and 40°C). Haematocrit did not influence DBS etoposide concentration. Good correlation between measured plasma and DBS concentrations was observed. The equation considering only haematocrit value was used for conversion of DBS to plasma concentration.
CONCLUSIONS: DBS sampling method showed comparable results to plasma samples. Therefore, it can be concluded that the developed and validated DBS method, which is more patient-friendly and requires less sample handling, is a reliable alternative to conventional plasma methods for measuring etoposide concentration in clinical pharmacological analyses.

Zhu Y, Wu Y, Zhang H, et al.
Enhanced Anti-Metastatic Activity of Etoposide Using Layered Double Hydroxide Nano Particles.
J Biomed Nanotechnol. 2015; 11(12):2158-68 [PubMed] Related Publications
Cell migration and invasion are integral to lung cancer metastasis. In this study, we investigated the combination of traditional chemotherapy and a layered double hydroxide (LDH) carrier as a new strategy for the inhibition of migration and invasion. To investigate the characteristics and possible mechanisms of VP16-LDH [the Mg-Al/LDH containing etoposide (VP16)], we used several experimental techniques, such as transmission electron microscopy (TEM) and fluorescent microscopy. The TEM, X-ray diffraction (XRD) and zeta potential results indicated that VP16 binds well with LDH, with an average size of 70 nm, and the drug delivery system was confirmed to have the desired quality of slow release by the in vitro release test results. Fluorescent images showed that the cellular uptake of VP16-LDH was a caveolae-mediated and energy-dependent process. Moreover, A549 cells treated with VP16-LDH (5 μg/ml, 10 μg/ml) demonstrated significant inhibition of cell migration and invasion compared with the cells treated with free VP16 at the same concentration. The inhibition of AKT, mTOR and STAT3 phosphorylation and p-β-catenin up-regulation in VP16-LDH-treated cells revealed a possible molecular mechanism via the mTOR/AKT and STAT pathways, through which VP16-LDH had a stronger inhibitory effect on migration than the drug alone.

Tonder M, Weller M, Eisele G, Roth P
Carboplatin and Etoposide in Heavily Pretreated Patients with Progressive High-Grade Glioma.
Chemotherapy. 2014; 60(5-6):375-8 [PubMed] Related Publications
BACKGROUND: Treatment of recurrent anaplastic glioma and glioblastoma remains a particular challenge in neurooncology. The lack of controlled trials results in poor evidence for all therapeutic options. Upon recurrence, many patients are treated with bevacizumab or one of the frequently used nitrosoureas such as lomustine. However, patients who still present in overall good condition after failure of multiple lines of therapy may ask for additional therapy.
METHODS: Here, we report our experience with the use of carboplatin in combination with etoposide as fourth- or fifth-line therapy in patients with progressive high-grade glioma.
RESULTS: The median Karnofsky performance status at the beginning of treatment was 80%. The median progression-free survival (PFS) was 2.5 months. PFS at 6 months was 0%. Administration of carboplatin and etoposide was associated with grade 3 or 4 hematotoxicity in 8 of 12 patients.
CONCLUSION: Carboplatin in combination with etoposide has an unfavorable risk-benefit profile in heavily pretreated glioma patients.

Srinivas R, Satterlee A, Wang Y, et al.
Theranostic etoposide phosphate/indium nanoparticles for cancer therapy and imaging.
Nanoscale. 2015; 7(44):18542-51 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Etoposide phosphate (EP), a water-soluble anticancer prodrug, is widely used for treatment of many cancers. After administration it is rapidly converted to etoposide, its parent compound, which exhibits anticancer activity. Difficulty in parenteral administration necessitates the development of a suitable nanoparticle delivery system for EP. Here we have used indium both as a carrier to deliver etoposide phosphate to tumor cells and as a SPECT imaging agent through incorporation of (111)In. Etoposide phosphate was successfully encapsulated together with indium in nanoparticles, and exhibited dose dependent cytotoxicity and induction of apoptosis in cultured H460 cancer cells via G2/M cell cycle arrest. In a mouse xenograft lung cancer model, etoposide phosphate/indium nanoparticles induce tumor cell apoptosis, leading to significant enhancement of tumor growth inhibition compared to the free drug.

Zhu R, Wang Q, Zhu Y, et al.
pH sensitive nano layered double hydroxides reduce the hematotoxicity and enhance the anticancer efficacy of etoposide on non-small cell lung cancer.
Acta Biomater. 2016; 29:320-32 [PubMed] Related Publications
UNLABELLED: 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.
STATEMENT OF SIGNIFICANCE: 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.

Kachalaki S, Baradaran B, Majidi J, et al.
Reversal of chemoresistance with small interference RNA (siRNA) in etoposide resistant acute myeloid leukemia cells (HL-60).
Biomed Pharmacother. 2015; 75:100-4 [PubMed] Related Publications
BACKGROUND: Overexpression of ATP-binding cassette (ABC) drug transporters is a major barrier in the success of cancer chemotherapy. One way to overcome overexpression of ABC drug transporter-mediated chemoresistance in acute myeloid leukemia is to suppress ABC drug transporter genes expression by small interference RNA (siRNA). In this study was assessed the involvement of ABCB1 gene in the mechanisms of resistance to etoposide in AML cells.
METHODS: The etoposide-resistant HL-60 cells were generated by stepwise exposure increasing concentrations of etoposide. The etoposide-resistant HL-60 cells were transfected with siRNAs using Transfection Reagent. The ABCB1 mRNA expression were assessed by real-time quantitative PCR. The MDR1/P-gp levels were measured by Western blotting. The sensitivity of resistant HL-60 cells to etoposide after transfection was determined using MTT assay. Apoptosis of resistant HL-60 cells after transfection was detected by flow cytometer.
RESULTS: It was found that siRNA effectively inhibited ABCB1 expression at both mRNA and protein levels. Knockdown of the ABCB1 gene correlated with increased sensitivity of the resistant HL-60 cells to etoposide and was observed to lower the cytotoxic index (IC50 etoposide value) after transfection.
CONCLUSIONS: Our results indicate that product of the ABCB1 gene have effective role in resistance to etoposide in acute myeloid leukemia cells.

Kizaki S, Hashimoto K, Matsui H, et al.
Comparison of 5-day MTX and 5-day ETP treatment results and early predictors of drug resistance to 5-day MTX in patients with post-molar low-risk gestational trophoblastic neoplasia.
Gynecol Oncol. 2015; 139(3):429-32 [PubMed] Related Publications
OBJECTIVE: To determine the primary remission rates and predictors of drug resistance in patients with post-molar low-risk gestational trophoblastic neoplasia (GTN) who were treated with a 5-day intramuscular methotrexate (5-day IM MTX) or a 5-day drip infusion etoposide (5-day DIV ETP) regimen.
METHODS: Between 1980 and 2014, 166 consecutive patients with low-risk post-molar GTN were initially treated with a 5-day IM MTX or a 5-day DIV ETP regimen. The primary remission rates, changes in chemotherapy due to drug resistance or toxicity, and relapse rates were compared. Furthermore, we analyzed the factors that influenced the development of resistance to MTX.
RESULTS: Primary remission rates were significantly higher among the ETP-treated patients than among the MTX-treated patients. Among the 42 patients who required a change in chemotherapy, 23 patients (22.6%) and 4 patients (6.3%) were diagnosed as being resistant to MTX and EPT, respectively. Maternal age and the presence of metastasis did not significantly influence the development of MTX resistance, although higher FIGO scores and pre-treatment human chorionic gonadotropin (hCG) levels of >5×10(4)mIU/mL were significantly more common among patients who developed MTX resistance. Moreover, a <30% decrease in hCG after the first cycles of MTX chemotherapy was significantly associated with the development of MTX resistance.
CONCLUSIONS: All patients with low-risk GTN eventually achieved complete remission, although several patients developed drug resistance to the first-line chemotherapy. A <30% decrease in hCG during the first chemotherapy cycle may be an early indicator of drug resistance after commencing a 5-day MTX regimen.

You B, Salles G, Bachy E, et al.
Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA).
Cancer Chemother Pharmacol. 2015; 76(5):939-48 [PubMed] Related Publications
BACKGROUND: Relationships between pharmacokinetic (PK) parameters of etoposide and toxicity survivals were reported in cancer patients treated at standard doses. The clinical impact of PK variations of etoposide high doses has never been explored in lymphoma patients.
PATIENTS AND METHODS: The primary objective of LYMPK study was to prospectively assess the impact of etoposide PK parameters on outcomes in lymphoma patients receiving high-dose chemotherapy regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). Individual etoposide PK parameters were estimated with a previously reported bi-compartment model using NONMEM(®) program. The impact of PK parameters on toxicity and survival was assessed using univariate/multivariate analyses.
RESULTS: A total of 91 patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL): 79; Hodgkin's lymphoma: 12] at first line (n = 49) or relapse (n = 42) were enrolled in five centers. Large inter-individual variabilities in individual PK values were found for the same administration doses. In NHL patients, cumulative higher trough concentrations over the eight administrations of the first cycle (TotC min, categorized by the median 58.71 mg/L) had significant prognostic value regarding the 5-year progression-free survival (PFS: 73.6 vs 46.5 %, P = 0.015) and 5-year overall survival (OS: 74.0 vs 52.2 %, P = 0.034). Using a Cox model analysis, integrating disease settings (first line vs recurrent disease), simplified IPI and other prognostic factors, TotC min was the only significant independent prognostic factor influencing PFS, disease-specific survival and OS.
CONCLUSION: This prospective study suggests survival of NHL patients treated with BEAM regimen and ASCT might be improved by increasing etoposide administration dose, or plasma concentration-based adjustment.

Zhou P, Liu P, Zhou SY, et al.
Ifosfamide, Cisplatin or Carboplatin, and Etoposide (ICE)-based Chemotherapy for Mobilization of Autologous Peripheral Blood Stem Cells in Patients with Lymphomas.
Chin Med J (Engl). 2015; 128(18):2498-504 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a promising approach for lymphomas. This study aimed to evaluate the effect of ifosfamide, cisplatin or carboplatin, and etoposide (ICE)-based regimen as a mobilization regimen on relapsed, refractory, or high-risk aggressive lymphoma.
METHODS: From June 2001 to May 2013, patients with lymphomas who mobilized by ICE-based regimen for ASCT were analyzed in this retrospective study. The results of the autologous peripheral blood stem cells collection, toxicity, engraftment after ICE-based mobilization regimen were analyzed in this study. Furthermore, risk factors for overall survival (OS) and progression free survival (PFS) were evaluated by univariate analysis.
RESULTS: The stem cells were mobilized using ICE-based regimen plus rituximab or ICE-based regimen alone in 12 patients and 54 patients, respectively. The results of stem cell mobilization were excellent. Ninety-seven percentages of the patients had the stem cell collection of at least 2.0 × 10 6 CD34 + cells/kg and 68% had at least 5 × 10 6 CD34 + cells/kg. Fifty-eight percentage of the patients experienced Grade 4 neutropenia, 20% developed febrile neutropenia, and only 12% had Grade 4 thrombocytopenia. At a median follow-up of 63.8 months, the 5-year PFS and OS were 64.4% and 75.3%, respectively.
CONCLUSION: ICE is a powerful regimen for stem cell mobilization in patients with lymphomas.

Wu F, Rom WN, Koshiji M, et al.
Role of GLI1 and NDRG1 in Increased Resistance to Apoptosis Induction.
J Environ Pathol Toxicol Oncol. 2015; 34(3):213-25 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
We examined the effects of GLI1 expression in PW mouse embryo fibroblasts and H441 lung carcinoma cells. Ectopic expression of GLI1 in PW cells induced anchorage-independent growth and increased resistance to staurosporine-induced apoptosis, and overexpression of GLI1 in H441 cells caused resistance to apoptosis induced by staurosporine and etoposide. GLI1 expression in both H441 and PW cells was associated with increased expression of NDRG1, a gene known to be downregulated by the MYC family of proteins, indicating that upregulation of NDRG1 by GLI1 is not cell-type specific. Consistent with suppression of NDRG1 by c-MYC and N-MYC, increased NDRG1 expression correlated with decreased expression of c-MYC and N-MYC in GLI1-expressing H441 and GLI1-expressing PW cells, respectively. Downregulation of GLI1 expression in A549 cells by siRNA transfection increased sensitivity to etoposide-induced apoptosis, and downregulation of NDRG1 expression in H441 cells by siRNA transfection increased sensitivity to etoposide-induced apoptosis. Of clinical significance, inhibition of GLI1 and NDRG1 expression may increase sensitivity of cancer cells to chemotherapeutic drugs. Strategies that aim to inhibit GLI1 function and NDRG1 expression may be useful for targeted therapy of cancers induced by the SHH-GLI signaling pathway.

Gadducci A, Lanfredini N, Cosio S
Reproductive outcomes after hydatiform mole and gestational trophoblastic neoplasia.
Gynecol Endocrinol. 2015; 31(9):673-8 [PubMed] Related Publications
Gestational trophoblastic disease includes complete hydatidiform mole (CHM) or partial hydatidiform mole (PHM) and gestational trophoblastic neoplasia (GTN). Given the very high-curability rate of trophoblastic disease, the risk of further molar pregnancy after CHM or PHM as well as the risk of second primary tumors and fertility compromise after chemotherapy for GTN represent major concerns. The incidence of subsequent molar pregnancy ranges from 0.7 to 2.6% after one CHM or PHM, and is approximately 10% after two previous CHMs. Among patients who have received chemotherapy, there is an increased risk of myeloid leukemia which is mainly related to the cumulative dose of etoposide. Resumption of normal menses occurs in approximately 95% of women treated with chemotherapy, but menopause occurs 3 years earlier compared with those non-treated with chemotherapy. Term live birth rates higher than 70% without increased risk of congenital abnormalities have been reported in these women, and pregnancy outcomes are comparable to those of general population, except a slightly increased risk of stillbirth. Fertility-sparing treatment for placental site trophoblastic tumor is a therapeutic option reserved to highly selected, young women who do not present markedly enlarged uterus or diffuse multifocal disease within the uterus.

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