OBJECTIVE: To establish a mouse model bearing orthotopic temozolomide (TMZ)-resistant glioma that mimics the development of drug resistance in gliomas METHODS: Seventy-eight adult C57BL/6 mice were randomly divided into 6 groups ( RESULTS: The mouse models bearing TMZresistant glioma was successfully established. The cells from the high-dose induced group showed a significantly higher colony-forming rate than those from the high-dose control group ( CONCLUSIONS Progressive increase of TMZ doses in mice bearing orthotopic gliomas can effectively induce TMZ resistance of the gliomas.
Animals ; Antineoplastic Agents, Alkylating/pharmacology* ; Brain Neoplasms/drug therapy* ; Cell Line, Tumor ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Glioma/drug therapy* ; Mice ; Mice, Inbred C57BL ; Temozolomide/therapeutic use*

In the present study, the effects of Pleurotus nebrodensis polysaccharide (PN-S) on the immune functions of immunosuppressed mice were determined. The immunosuppressed mouse model was established by treating the mice with cyclophosphamide (40 mg/kg/2d, CY) through intraperitoneal injection. The results showed that PN-S administration significantly reversed the CY-induced weight loss, increased the thymic and splenic indices, and promoted proliferation of T lymphocyte, B lymphocyte, and macrophages. PN-S also enhanced the activity of natural killer cells and increased the immunoglobulin M (IgM) and immunoglobulin G (IgG) levels in the serum. In addition, PN-S treatment significantly increased the phagocytic activity of mouse peritoneal macrophages. PN-S also increased the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), and nitric oxide (NOS) in splenocytes. qRT-PCR results also indicated that PN-S increased the mRNA expression of IL-6, TNF-α, INF-γ, and nitric oxide synthase (iNOS) in the splenocytes. These results suggest that PN-S treatment enhances the immune function of immunosuppressed mice. This study may provide a basis for the application of this fungus in adjacent immunopotentiating therapy against cancer and in the treatment of chemotherapy-induced immunosuppression.
Animals ; Antineoplastic Agents, Alkylating ; Biological Products ; pharmacology ; therapeutic use ; Cell Line ; Cyclophosphamide ; Immunity ; drug effects ; Immunologic Factors ; pharmacology ; therapeutic use ; Immunosuppression ; Interferon-gamma ; metabolism ; Interleukin-6 ; metabolism ; Macrophages ; drug effects ; metabolism ; Male ; Mice, Inbred BALB C ; Neoplasms ; drug therapy ; immunology ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type II ; metabolism ; Phagocytosis ; drug effects ; Pleurotus ; chemistry ; Polysaccharides ; pharmacology ; therapeutic use ; Tumor Necrosis Factor-alpha ; metabolism

Epithelial ovarian cancer (OC) is a common gynecologic malignancy in women. The standard treatment for OC is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. Despite the high response rate to primary therapy, approximately 85% of patients will develop recurrent ovarian cancer (ROC). This review identifies the clinical use of trabectedin in the treatment algorithm for ROC, with specific emphasis on platinum-sensitive ROC, for which trabectedin in combination with pegylated liposomal doxorubicin has been approved as a treatment protocol. The main mechanisms of action of trabectedin at the cellular level and in the tumor microenvironment is also discussed as bases for identifying biomarkers for selecting patients who may largely benefit from trabectedin-based therapies.
Antineoplastic Agents, Alkylating ; therapeutic use ; Clinical Trials as Topic ; DNA Damage ; Dioxoles ; administration & dosage ; pharmacology ; therapeutic use ; Doxorubicin ; administration & dosage ; analogs & derivatives ; Female ; Humans ; Neoplasm Recurrence, Local ; drug therapy ; Neoplasms, Glandular and Epithelial ; drug therapy ; Ovarian Neoplasms ; drug therapy ; Polyethylene Glycols ; administration & dosage ; Tetrahydroisoquinolines ; administration & dosage ; pharmacology ; therapeutic use ; Tumor Microenvironment

Although methyltransferase has been recognized as a major element that governs the epigenetic regulation of the genome during temozolomide (TMZ) chemotherapy in glioblastoma multiforme (GBM) patients, its regulatory effect on glioblastoma chemoresistance has not been well defined. This study investigated whether DNA methyltransferase (DNMT) expression was associated with TMZ sensitivity in glioma cells and elucidated the underlying mechanism. DNMT expression was analyzed by western blotting. miR-20a promoter methylation was evaluated by methylation-specific PCR. Cell viability and apoptosis were assessed using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and TdT-mediated dUTP-biotin nick end labeling assays, respectively. The results showed that compared with parental U251 cells, DNMT1 expression was downregulated, miR-20a promoter methylation was attenuated and miR-20a levels were elevated in TMZ-resistant U251 cells. Methyltransferase inhibition by 5-aza-2\'-deoxycytidine treatment reduced TMZ sensitivity in U251 cells. In U251/TM cells, DNMT1 expression was negatively correlated with miR-20a expression and positively correlated with TMZ sensitivity and leucine-rich repeats and immunoglobulin-like domains 1 expression; these effects were reversed by changes in miR-20a expression. DNMT1 overexpression induced an increase in U251/TM cell apoptosis that was inhibited by the miR-20a mimic, whereas DNMT1 silencing attenuated U251/TM cell apoptosis in a manner that was abrogated by miR-20a inhibitor treatment. Tumor growth of the U251/TM xenograft was inhibited by pcDNA-DNMT1 pretreatment and boosted by DNMT1-small hairpin RNA pretreatment. In summary, DNMT1 mediated chemosensitivity by reducing methylation of the microRNA-20a promoter in glioma cells.
Animals ; Antineoplastic Agents, Alkylating/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Brain/drug effects/metabolism/pathology ; Brain Neoplasms/drug therapy/*genetics/pathology ; DNA (Cytosine-5-)-Methyltransferase/antagonists & inhibitors/*genetics/metabolism ; DNA Methylation ; Dacarbazine/*analogs & derivatives/pharmacology/therapeutic use ; Drug Resistance, Neoplasm ; Female ; Gene Expression Regulation, Neoplastic ; Glioma/drug therapy/*genetics/pathology ; Humans ; Mice, Inbred C57BL ; MicroRNAs/*genetics ; Promoter Regions, Genetic

AIMTo evaluate the effect of polysaccharide from Spirulina platensis (PSP) on hematopoietic cell proliferation, apoptosis and Bcl-2 expression in mice bearing tumor treated with chemotherapy.

METHODSThe model of chemotherapy for transplant solid tumor in mice was established. The hematopoietic cell proliferation, apoptosis, Bcl2 expression and related cytokines were assayed by the technique of culture of hematopoietic progenitor cell, fluoromicroscope and light microscope, immunohistochemical method, and double antibody sandwich ELISA.

RESULTSPSP significantly ameliorated CFU-GM proliferation inhibition and hematopietic cells apoptosis induced by CTX. Moreover, PSP evidently increased the content of IL-1, IL-3, GM-CSF and TNF-alpha in serum and Bcl-2 expression of hematopoietic cells.

CONCLUSIONPSP indirectly upregulated Bcl-2 expression of hematopoietic cells by promoting endogenous cytokines secretion which may be one of the mechanisms, by which PSP enhanced hematopoietic cell proliferation and inhibited its apoptosis in mice bearing tumor treated with chemotherapy.

Animals ; Antineoplastic Agents, Alkylating ; therapeutic use ; Apoptosis ; Bacterial Proteins ; chemistry ; Cell Division ; drug effects ; Cyclophosphamide ; therapeutic use ; Female ; Hematopoietic Stem Cells ; drug effects ; pathology ; Liver Neoplasms, Experimental ; drug therapy ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred ICR ; Polysaccharides ; isolation & purification ; pharmacology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Random Allocation ; Spirulina