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- Upregulation of Stat1-HDAC4 confers resistance to etoposide through enhanced multidrug resistance 1 expression in human A549 lung cancer cells. [JOURNAL ARTICLE]
- Mol Med Rep 2014 Nov 14.
Despite efforts to develop efficient chemotherapeutic drug strategies to treat cancer, acquired drug resistance is a commonly encountered problem. In the present study, to investigate this phenomenon, human A549 lung cancer cells resistant to the topoisomerase inhibitor etoposide (A549RT‑eto) were used and compared with A549 parental cells. A549RT‑eto cells demonstrated increased resistance to etoposide‑induced apoptosis when compared with A549 parental cells. Notably, A549RT‑eto cells were observed to exhibit greater levels of histone deacetylase 4 (HDAC4), phospho‑Stat1 and P‑glycoprotein [P‑gp; encoded by the multidrug resistance 1 (MDR1) gene], compared with A549 cells. To address whether HDAC4 protein is involved in etoposide resistance in A549 cells, A549RT‑eto cells were treated with trichostatin A (TSA; an HDAC inhibitor) during etoposide treatment. The combined treatment was demonstrated to enhance etoposide‑induced apoptosis and reduce expression levels of HDAC4, P‑gp and phospho‑Stat1. In addition, the suppression of Stat1 with siRNA enhanced etoposide‑induced apoptosis and reduced the expression levels of HDAC4 and P‑gp, suggesting that Stat1 is essential in the regulation of resistance to etoposide, and in the upregulation of P‑gp. Notably, TSA treatment reduced P‑gp transcript levels but Stat1 siRNA treatment did not, suggesting that P‑gp is regulated by HDAC at the transcriptional level and by Stat1 at the post‑transcriptional level. These results suggest that the upregulation of Stat1 and HDAC4 determines etoposide resistance through P‑gp expression in human A549 lung cancer cells.
- Haemophagocytic syndrome and elevated EBV load as initial manifestation of Hodgkin lymphoma in a HIV patient: case report and review of the literature. [Journal Article]
- J Int AIDS Soc 2014; 17(4 Suppl 3):19650.
In HIV patients, haemophagocytic syndrome (HPS) may occur in the presence of cancer, concomitant viral infection, HIV primo-infection or at the initiation of highly active antiretroviral therapy (HAART). Hodgkin lymphoma remains a rare cause of HPS. We describe a case of HPS with very high Epstein Barr virus (EBV) load in a HIV patient as initial manifestation of Hodgkin lymphoma.A 29-year-old HIV positive man, successfully treated with HAART with an undetectable viral load and CD4 cells count of 438/µl, was admitted for high fever of unknown origin. Laboratory results showed a pancytopenia with haemoglobin at 82 g/l, lymphocyte count at 0.36G/l and platelets count at 47G/l; a highly elevated ferritine >7500 µg/l; increased lactate dehydrogenase at 885U/l and soluble IL2 receptor (CD25) >60 ng/ml. EBV load was measured and confirmed at 2,600,000 copies/ml. A PET-CT imaging showed diffuse elevated metabolic activity in the bone marrow and in two lesions in the spleen without lymphadenopathy. Bone marrow and liver biopsies revealed images of haemophagocytosis and lymphocyte depleted Hodgkin lymphoma. Treatment consisted in etoposid, steroids, and R-ABVD (rituximab, doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy. The patient completed six cycles of chemotherapy. We reviewed the literature in PubMed with the following keywords: HPS, HIV, EBV, Hodgkin lymphoma.We identified four publications and two reviews reporting cases of HPS associated with Hodgkin lymphoma in HIV patients with either a positive EBV load either the presence of encoded EBV RNA in tumour cells. Twenty-two cases (including one pediatric case) were described. Among adults, mostly men, the median age was <50 years and immune suppression was marked with a median CD4 cell count<100 cells/µl, even in patients receiving HAART. When measured, EBV load in the serum was high. Prognosis was poor with a high mortality despite adequate treatment consisting in steroids and chemotherapy, with or without etoposide (Table 1).Our case report and the review of literature suggest that physicians should be aware of the association between EBV infection/reactivation and Hodgkin lymphoma as a cause of HPS in HIV patients, even if successfully treated with HAART. The pathogenesis of these three interrelated conditions (viral infection, oncogenesis and immunologic reaction) remains unclear.
- Zoledronic acid induces apoptosis and S-phase arrest in mesothelioma through inhibiting Rab family proteins and topoisomerase II actions. [Journal Article]
- Cell Death Dis 2014.:e1517.
Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, produced anti-tumor effects through apoptosis induction or S-phase arrest depending on human mesothelioma cells tested. An addition of isoprenoid, geranylgeraniol but not farnesol, negated these ZOL-induced effects, indicating that the ZOL-mediated effects were attributable to depletion of geranylgeranyl pyrophosphates which were substrates for prenylation processes of small guanine-nucleotide-binding regulatory proteins (small G proteins). ZOL-treated cells decreased a ratio of membrane to cytoplasmic fractions in RhoA, Cdc42 and Rab6 but less significantly Rac1 proteins, indicating that these proteins were possible targets for ZOL-induced actions. We further analyzed which small G proteins were responsible for the three ZOL-induced effects, caspase-mediated apoptosis, S-phase arrest and morphological changes, using inhibitors for respective small G proteins and siRNA for Cdc42. ZOL-induced apoptosis is due to insufficient prenylation of Rab proteins because an inhibitor of geranlygeranyl transferase II that was specific for Rab family proteins prenylation, but not others inhibitors, activated the same apoptotic pathways that ZOL did. ZOL suppressed an endogenous topoisomerase II activity, which was associated with apoptosis and S-phase arrest in respective cells because we detected the same cell cycle changes in etoposide-treated cells. Inhibitors for geranlygeranyl transferase I and for RhoA produced morphological changes and disrupted actin fiber structures, both of which were similar to those by ZOL treatments. These data demonstrated that anti-tumor effects by ZOL were attributable to inhibited functions of respective small G proteins and topoisomerase II activity, and suggested that cellular factors were involved in the differential cell cycle changes.Cell Death and Disease advance online publication, 13 November 2014; doi:10.1038/cddis.2014.475.
- Long term outcome of patients with clinical stage I high-risk nonseminomatous germ cell tumors 15 years after one adjuvant cycle of Bleomycin, Etoposide and Cisplatin chemotherapy. [JOURNAL ARTICLE]
- Ann Oncol 2014 Nov 12.
To report the long-term results of adjuvant treatment with 1 cycle of modified bleomycin, etoposide, and cisplatin (BEP) in patients with clinical stage I (CS I) nonseminomatous germ cell tumors (NSGCT) at high risk of relapse.In a single-arm, phase II clinical trial, 40 patients with CS I NSGCT with vascular invasion and/or >50% embryonal cell carcinoma in the orchiectomy specimen received one cycle of adjuvant BEP (20 mg/m(2) bleomycin as a continuous infusion over 24 hours, 120 mg/m(2) etoposide and 40 mg/m(2) cisplatin each on days 1-3). Primary endpoint was the relapse rate.Median follow-up was 186 months. One patient (2.5%) had a pulmonary relapse 13 months after 1 BEP and died after 3 additional cycles of BEP chemotherapy. Three patients (7.5%) presented with a contralateral metachronous testicular tumor, and 3 (7.5%) developed a secondary malignancy. 3 patients (7.5%) reported intermittent tinnitus and 1 had grade 2 peripheral polyneuropathy (2.5%).Adjuvant chemotherapy with 1 cycle of modified BEP is a feasible and safe treatment for patients with CS I NSGCT at high risk of relapse. In these patients it appears to be an alternative to 2 cycles of BEP and to have a lower relapse rate than retroperitoneal lymph node dissection (RPLND). If confirmed by other centers, 1 cycle of adjuvant BEP chemotherapy should become a first line treatment option for this group of patients.
- The Role of Chemotherapy for Metastatic, Relapsed and Refractory Osteosarcoma. [JOURNAL ARTICLE]
- Paediatr Drugs 2014 Nov 13.
Despite a large number of publications on outcomes of second-line chemotherapy for osteosarcoma, there is little consensus on efficacy of the therapy.Our objective was to systematically categorize published evidence for chemotherapy for metastatic, relapsed and refractory osteosarcoma in order to provide an updated and comprehensive analysis of the clinical outcomes.We performed a search of PubMed and EMBASE to identify published articles reporting on validated clinical outcomes measures (the rate of complete response [CR] and partial response [PR], the rate of stable disease [SD] and progressive disease [PD] and the 5-year overall survival) after chemotherapy in patients with metastatic, relapsed and refractory osteosarcoma. A total of 20 articles were identified and stratified by different regimens. Finally, six regimens that have at least two drugs were reviewed. Weighted averages of each outcome were computed.The weighted average overall response rate (CR + PR) for the combination of ifosfamide, etoposide and high-dose methotrexate therapy was 62 %, and the tumor control rate (CR + PR + SD) was 92.3 %; the highest of all six regimens. The weighted average overall response rate and tumor control rate of ifosfamide-etoposide therapy (41.7 and 77.9 %, respectively) were the highest of the two-drug regimens. Weighted average overall response rate and tumor control rate for the remaining regimens were 20.5 and 56.8 %, respectively, for cyclophosphamide-etoposide; 30.0 and 73.5 % for ifosfamide, carboplatin, and etoposide; 12.0 and 40.0 % for cyclophosphamide-topotecan; and 14.5 and 36.4 % for gemcitabine-docetaxel.A chemotherapy regimen comprising both a cell cycle-specific drug and a cell cycle-nonspecific drug could increase response rates. The combination of ifosfamide and etoposide therapy is our first choice in two-drug regimens. Regarding three-drug regimens, adding a cell cycle-specific drug to ifosfamide-etoposide therapy may result in a better response rate than adding a cell cycle-nonspecific drug, or any other two-drug regimens in current studies. Hence, we recommend the use of second-line chemotherapy based on the combination ifosfamide-etoposide regimen in patients with metastatic, relapsed and refractory osteosarcoma.
- A novel trial of topotecan, ifosfamide, and carboplatin (TIC) in children with recurrent solid tumors. [JOURNAL ARTICLE]
- Pediatr Blood Cancer 2014 Nov 8.
Ifosfamide, carboplatin, and etoposide (ICE) in children with refractory or recurrent solid tumors and lymphomas has resulted in good overall response rates (ORR). Etoposide, a topoisomerase-II inhibitor, however, has been associated with a significant increase in secondary leukemia. The rationale for substituting topotecan, a topoisomerase-I inhibitor, for etoposide in this regimen, a topoisomerase-II inhibitor, includes its limited toxicity profile and decreased leukemogenicity. Furthermore, topotecan in combination with both alkylators and platinating agents are additive and/or synergistic against a variety of solid tumors.Patients with relapsed/refractory solid tumors received ifosfamide (9 g/m(2) ) and carboplatin (area under the curve: 3 mg/ml/min). Topotecan was also administered at 0.5 mg/m(2) /day × 3 days (N = 12) and in a small cohort (N = 3) at 0.75 mg/m(2) /day.Fifteen patients were entered onto study. Two patients developed seizures/encephalitis secondary to ifosfamide. One patient had dose-limiting thrombocytopenia secondary to TIC that resolved with supportive care. Patients received a median of three cycles (1-3) of TIC. Of the 14 evaluable patients for response, 4/14 had a complete response (CR), 2/14 had a partial response (PR), and 1/14 patients had stable disease (SD). The ORR (CR + PR) was 43%.TIC chemotherapy is feasible and tolerable in children and adolescents with refractory/recurrent solid tumors and lymphomas and results in a 43% excellent ORR in this poor-risk group of patients. A larger cohort of patients, especially in Wilms tumor and central nervous system (CNS) tumors, should be studied in the future to attempt to confirm these preliminary findings. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
- Conventional Cisplatin-Based Combination Chemotherapy Is Effective in the Treatment of Metastatic Spermatocytic Seminoma with Extensive Rhabdomyosarcomatous Transformation. [JOURNAL ARTICLE]
- Cancer Res Treat 2014 Sep 11.
A 52-year-old man was presented with a huge left testicular mass and palpable cervical lymphadenopathy with retroperitoneal lymph node enlargement on an abdominal computed tomography. A left radical orchiectomy and an ultrasound-guided neck node biopsy were performed. A pathological examination revealed spermatocytic seminoma with extensive rhabdomyosarcomatous transformation, a condition known to be highly resistant to platinum-based chemotherapy. The patient received four cycles of etoposide, ifosfamide and cisplatin (VIP) chemotherapy. A repeat computed tomography revealed a substantial regression consistent with a partial response. Retroperitoneal lymph node dissection was attempted, which revealed rhabdomyosarcoma; however, complete microscopic resection was not achieved. After surgery, the residual abdominal lymph node progressed and salvage paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy was employed, which again achieved a partial response. Here, we present a first case report of a spermatocytic seminoma with extensive rhabdomyosarcomatous transformation and multiple metastatic lymphadenopathies that showed a favorable response to platinum-based systemic chemotherapy.
- Treatment strategies and long-term outcomes for primary intramedullary spinal germinomas: an institutional experience. [JOURNAL ARTICLE]
- J Neurooncol 2014 Nov 9.
Primary intramedullary germinomas are very rare tumors in the spinal cord. This study presented a series of 11 patients with histologically proven primary intramedullary spinal germinomas. Their clinical and radiological findings, treatment records and long-term outcomes were reviewed. There were four male and seven female patients with a mean age of 27.1 years. Because germ cell tumors were suspected by frozen-section biopsy, gross total resection was unattempted. Partial resection was performed in four cases, while biopsy was performed in seven cases. Postoperatively, carboplatin and etoposide chemotherapy combined with low dose radiotherapy (30.6 Gy) to local spine was performed in seven cases, followed by radiotherapy alone (40 Gy) in four cases. All 11 patients had a complete response to either combination treatment or single radiotherapy, and the mass effect on the spinal cord vanished. The mean follow-up period was 75.4 months. At the last follow-up, the symptoms were improved in 10 cases and the current status of one patient was unchanged. The postoperative follow-up magnetic resonance imaging showed no recurrence or dissemination in any of the patients. Primary intramedullary germinomas are amenable to adjuvant radiochemotherapy and low dose radiation with etoposide and carboplatin chemotherapy is recommended. When combination therapy cannot be performed, relatively high doses of radiotherapy are advised, and radiation to the craniospinal axis may be unnecessary. A good clinical outcome after combination therapy or radiotherapy alone can be expected, and the risk of long-term recurrence and dissemination is low.
- Biosimilar granulocyte colony-stimulating factor is effective in reducing the duration of neutropenia after autologous peripheral blood stem cell transplantation. [Journal Article]
- Transplant Proc 2014; 46(8):2882-4.
Autologous peripheral blood stem cell transplantation (APBSCT) is the standard of therapy for patients with multiple myeloma and refractory Hodgkin's and non-Hodgkin's lymphomas. Granulocyte colony-stimulating factor (G-CSF) is widely used to accelerate hematopoietic recovery after transplantation and to reduce the morbidity and mortality associated with prolonged neutropenia. Biosimilar G-CSF is approved for the same indications as the originator G-CSF. This is one of the first reported uses of a biosimilar G-CSF for neutrophil recovery after APBSCT.A total of 23 consecutive patients with hematological malignancy (multiple myeloma, Hodgkin's and non-Hodgkin's lymphomas, and acute myelogenous leukemia) were recruited at the Department of Haematooncology and Bone Marrow Transplantation at the Medical University of Lublin. Patients (12 men and 11 women; median age, 47 ± 13 years) received biosimilar G-CSF (Zarzio, Sandoz Biopharmaceuticals) after myeloablative chemotherapy (primarily BiCnU, etoposide, cytarabine, and melphalan or melphalan 140/200 mg/m(2)) followed by PBSCT. The median number of transplanted CD34+ cells was 4.2 ± 0.8 × 10(6)/kg body wt. G-CSF therapy was started when absolute neutrophil count (ANC) was <0.5 × 10(9)/L and was continued until ANC reached >1.5 × 10(9)/L for 3 consecutive days. Hematopoietic recovery parameters were compared with those in the control group, which consisted of 23 consecutive patients transplanted in the period before the biosimilar G-CSF group and receiving originator G-CSF (Neupogen, Amgen).The mean duration of treatment with biosimilar and originator G-CSF was 14.4 ± 5.1 and 18.6 ± 11.5 days, respectively (P = .43). The adverse event profile was comparable between the biosimilar G-CSF and originator G-CSF groups, with similar occurrence of neutropenic fever (5 versus 6 patients) and bone pain (7 patients in each group). One patient in the biosimilar group had neutropenic enterocolitis and sepsis. There was no case of death in either group. Granulocyte recovery in the study group was as follows: mean days to ANC >0.5 × 10(9)/L was 13.0 ± 4.0 days; to ANC >1.5 × 10(9)/L, 13.6 ± 4.5 days; and to ANC >1.5 × 10(9)/L, 14.0 ± 4.7 days. Mean duration until platelet recovery >20 × 10(9)/L was 16.1 ± 4.4 days. There were no statistically significant differences between the biosimilar and originator G-CSF groups in hematopoietic recovery parameters.Biosimilar G-CSF is safe and effective in reducing the duration of neutropenia in patients undergoing myeloablative therapy followed by APBSCT and probably in cost savings in transplantation budgets.
- Mangiferin activates the Nrf2-ARE pathway and reduces etoposide-induced DNA damage in human umbilical cord mononuclear blood cells. [JOURNAL ARTICLE]
- Pharm Biol 2014 Nov 7.:1-9.
Abstract Context: Mangiferin (2-C-β-d-gluco-pyranosyl-1,3,6,7-tetrahydroxyxanthone) is a well-known natural antioxidant distributed in various plants of the Anacardiaceae and Gentianaceae families. Mangiferin can inhibit carcinogen-induced lung or colon tumor formation in experimental animals. However, the molecular mechanisms of its chemopreventive activity remain unexplored. Objective: This study aimed to investigate the effects of mangiferin on chemical carcinogen-induced DNA damage and Nrf2-ARE signaling in hematopoietic cells. Materials and methods: Mononuclear cells (MNCs) were isolated from human umbilical cord blood (hUCB). DNA damage was evaluated by comet and micronucleus assays. The expression of Nrf2 and NQO1 was examined by immunofluorescence and western blotting. An electrophoretic mobility shift assay (EMSA) was used to detect the binding activity of Nrf2 with NQO1-ARE sequences. Results: We found that mangiferin treatment significantly reduced DNA damage in etoposide-treated MNCs, which was verified by decreased olive tail moment (OTM) and micronucleus (MN) frequency. Mangiferin treatment significantly promoted Nrf2 translocation into the nucleus and increased nuclear Nrf2 expression. Moreover, NQO1, an Nrf2 signaling target, was significantly upregulated by mangiferin treatment, and the binding activity of Nrf2 with NQO1-ARE sequences was elevated after mangiferin treatment. Discussion and conclusion: Mangiferin activated Nrf2 signaling, upregulated NQO1 expression, and significantly reduced etoposide-induced DNA damage. Thus, mangiferin is a potential cytoprotective agent for hematopoietic cells.