In vitro antitumor effect of sodium butyrate and zoledronic acid combined with traditional chemotherapeutic drugs : a paradigm of synergistic molecular targeting in the treatment of Ewing sarcoma

Histone deacetylase inhibitors and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, particularly when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been systematically evaluated in Ewing sarcoma. The in vitro effects on cellular proliferation, viability and survival were investigated in two Ewing sarcoma cell lines, SK-ES-1 and RD-ES. The cell lines were treated with sodium butyrate, a histone deacetylase inhibitor and zoledronic acid, a bisphosphonate, alone, together or in combination with chemotherapeutic drugs recommended for clinical treatment of Ewing sarcoma. The data demonstrated that the combination of sodium butyrate and zoledronic acid had a synergistic cytotoxic effect at 72 h following treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between sodium butyrate or zoledronic acid and the traditional antineoplastic drugs (doxorubicin, etoposide and vincristine) demonstrated a synergistic cytotoxic effect at 72 h in SK-ES-1 and RD-ES cells, except for the combinations of sodium butyrate with vincristine and of zoledronic acid with doxorubicin, which showed only an additive effect in RD-ES cell lines as compared to each agent alone. These acute effects observed in both Ewing sarcoma cell lines were confirmed by the clonogenic assay. The present data suggest that combining histone deacetylase inhibitors and bisphosphonates with traditional chemotherapeutic drugs is a promising therapeutic strategy for the treatment of Ewing sarcoma, and provides a basis for further studies in this field

Efeitos do bloqueio de receptores GRPR sobre o crescimento de gliomas humanos in vitro

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De-mystifying the epigenetic free for all : pharmacophore modeling for epigenetic cancer therapy

Epigenetic regulators have quickly become one of the most widely studied therapeutic agents for a vast array of diseases, making histone deacetylase inhibitors (HDIs) and DNA methyl-transferase (DNMT) inhibitors commonly used molecules in pre-clinical and clinical anti-cancer studies. Their ability to regulate gene expression and to potentiate the effects of other chemotherapeutic drugs has put HDIs and DNMT inhibitors in the spotlight not only as single agents, but also as combined therapy. The plethora of HDIs and DNMT inhibitors available nowadays has led to promising results in Phase I, II and III clinical oncology studies. While it was first believed that these molecules would all have an additive or synergistic effect when combined with the classical chemotherapeutic drugs available, our group and others have shown that epigenetic regulators potentiate the effects of some, but not all, anti-cancer molecules. Pharmacophore modeling may therefore serve the purpose to optimize pre-clinical research and to develop more efficient and targeted therapies incorporating epigenetic regulators

EHMT2/G9a as an epigenetic target in pediatric and adult brain tumors

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors

Gene expression changes associated with chemotherapy resistance in Ewing sarcoma cells

Ewing Sarcoma (ES) is a highly aggressive bone and soft tissue childhood cancer. The development of resistance to chemotherapy is common and remains the main cause of treatment failure. We herein evaluated the expression of genes associated with chemotherapy resistance in ES cell lines. A set of genes (CCAR1, TUBA1A, POLDIP2, SMARCA4 and SMARCB1) was data-mined for resistance against doxorubicin and vincristine, which are the standard drugs used in the treatment of patients with ES. The expression of each gene in SK-ES-1 ES cells was reported before and after exposure to a drug resistance-inducing protocol. There was a significant downregulation of CCAR1 and TUBA1A in doxorubicin-resistant cells, with low expression of TUBA1A in vincristine-resistant cells. By contrast, POLDIP2 was significantly upregulated in cells resistant to either drug, and the expression of the SMARCB1 and SMARCA4 genes was upregulated in doxorubicin-resistant cells. These findings indicate that resistance to specific chemotherapeutic agents was accompanied by differential changes in gene expression in ES tumors

Exposição ocupacional a drogas antineoplásicas : condutas para manipulação segura

As drogas antineoplásicas são utilizadas de forma crescente no meio hospitalar devido aos promissores resultados apresentados no tratamento do câncer. As ações desejadas destas drogas, principalmente suas capacidades citotóxica/citostática e imunomoduladora, são obtidas às custas de efeitos colaterais freqüentemente severos. Um aspecto pouco abordado em nosso meio no espectro do uso de drogas antineoplásicas é a questão do manejo e administração dessas drogas. A maioria dos profissionais de saúde não se sente adequadamente esclarecida sobre os riscos potenciais dos fármacos a serem manipulados. Neste artigo analisa- se a questão da exposição ocupacional a drogas antineoplásicas no meio hospitalar, no sentido de orientar a equipe de saúde quanto aos cuidados a serem tomados na manipulação de quimioterápicos, e aos riscos potenciais e reais a que são submetidos

Clinical and pharmacokinetic study of fractionated doses of oral etoposide in pediatric patients with advanced malignancies

The purpose of this phase I study was to evaluate the toxicity profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and plasma pharmacokinetics of oral etoposide, and to recommend a safe fractionated dose for phase II trials in pediatric patients with refractory solid tumors. Material/Methods: All patients had tumors no longer amenable to established forms of treatment. The initial dose of etoposide was 20 mg/m2 TID for 14 days every 21 days (dose-level I). Etoposide plasma pharmacokinetics were studied on day 1 of treatment and determined by HPLC. Results: Seventeen children were enrolled, 13 of whom were included in the pharmacokinetic study, for a total of 64 courses. Nine patients were included at dose-level I; grade 2–3 leucopenia was observed in 5. The dose was then raised to 25 mg/m2 (dose-level II) in another 8 patients; grade 3–4 leucopenia was observed in 4. This dose-level was therefore considered the MTD. The DLT was neutropenia. In patients at dose-level I and II the maximum plasma etoposide concentration was 2.97 and 8.59 μg/ml, respectively. Drug levels > 1 μg/ml were maintained for about 6.3 hours following drug administration at both dose-levels. Partial response was observed in 1 patient and 4 patients showed stable disease. Conclusions: Prolonged oral etoposide was well tolerated by our patients. Considering the MTD, and the fact that the patients included at dose-level I achieved an adequate (>1 μg/ml) plasma concentration of etoposide for a sufficient time, this dose level was recommended for phase II studies in pediatric malignancies. This work was performed at the Pediatric Oncology Service, Hospital de Clínicas de Porto Alegre; the Pediatric Hematology-Oncology Service, Hospital da Crianca Conceicao; and at the South American Office for Anticancer Drug Development (SOAD), Porto Alegre, Brazil