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1.
Article in Chinese | WPRIM | ID: wpr-880829

ABSTRACT

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.


Subject(s)
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
2.
Article in English | WPRIM | ID: wpr-215492

ABSTRACT

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.


Subject(s)
Animals , Antineoplastic Agents, Alkylating/pharmacology , Apoptosis/drug effects , Brain/drug effects , Brain Neoplasms/drug therapy , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA Methylation , Dacarbazine/analogs & derivatives , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic , Glioma/drug therapy , Humans , Mice, Inbred C57BL , MicroRNAs/genetics , Promoter Regions, Genetic
3.
Rev. bras. parasitol. vet ; 23(4): 530-533, Oct-Dec/2014. graf
Article in English | LILACS | ID: lil-731248

ABSTRACT

Here we describe an outbreak of chorioptic mange in cattle, 56 years after its first identification in Brazil. Between the months of June and July 2011, dermatitis characterized by alopecia and crusted and thickened skin at the insertion of the tail and in the ischiorectal fossa was recognized in 40 (35.7%) out of 112 Holstein cows on a farm in the northeastern mesoregion of the state of Rio Grande do Sul, Brazil. After diagnosing mange caused by Chorioptes bovis, the cows were weighed and treated with 0.5% ivermectin, as a pour-on single dose, and were separated into two groups: cows in early lactation and those in late lactation. The survival rate of C. bovis and the healing rate in the two groups of infested cows were monitored every seven days through skin scrapings. After 28 days of evaluation, the cure rate through treatment was greater among cows in early lactation (p <0.0001). The survival rate of C. bovis was higher in cows in late lactation.


O objetivo deste estudo foi descrever um surto de sarna corióptica em bovinos, 56 anos após a sua primeira identificação no Brasil. Entre os meses de junho a julho de 2011, a dermatite caracterizada por alopecia, com crosta e espessamento da pele na inserção da cauda e na fossa isquiorretal, foi observada em 40 (35,7%) de 112 vacas holandesas de uma propriedade rural pertencente à Mesorregião do Nordeste do Estado do Rio Grande do Sul, Brasil. Após o diagnóstico da sarna causada por Chorioptes bovis, as vacas foram pesadas, tratadas com 0,5% de ivermectina pour on em dose única e separadas em dois grupos: vacas no início da lactação e no final da lactação. A taxa de sobrevivência de C. bovis e a taxa de cura dos dois grupos de vacas infestadas foram monitoradas a cada sete dias por meio de raspas de pele. Após 28 dias do estudo, a taxa de cura com o tratamento foi maior em vacas no início da lactação (p <0,0001). A taxa de sobrevivência de C. bovis foi maior em vacas no final da lactação.


Subject(s)
Animals , Female , Male , Mice , Air Pollutants/toxicity , Bone Marrow Cells/drug effects , Micronuclei, Chromosome-Defective/drug effects , Sulfur Dioxide/toxicity , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents, Alkylating/pharmacology , Cyclophosphamide/pharmacology , Dose-Response Relationship, Drug , Dimethyl Sulfoxide/pharmacology , Erythrocytes/drug effects , Mitomycin/pharmacology , Sulfites/toxicity
4.
Indian J Exp Biol ; 2013 Aug; 51(8): 615-622
Article in English | IMSEAR | ID: sea-149364

ABSTRACT

Oxazaphosphorines belong to a group of alkylating agents. Mafosfamide cyclohexylamine salt (D-17272), 4-hydro-peroxy-cyclophosphamide (D-18864) and glufosfamide (D-19575, β-D-glucose-isophosphoramide mustard) are new generation oxazaphosphorines. The objective of the present study was to compare the cytotoxic action of these oxazaphosphorine compounds against human histiocytic lymphoma U937 cells. The chemical structures of the oxazaphosphorines were responsible for the different responses of U937 cells. The cytotoxic effects of D-17272, D-18864, and D-19575 on U937 cells depended on the agent tested, its dose, and the time intervals after the oxazaphosphorine application. Among the oxazaphosphorine agents, D-18864 appeared to be the most cytotoxic, and D-19575 was characterized by the lowest cytotoxicity. The in vitro cytotoxic activities of the oxazaphosphorines were strongly associated with their cell death inducing potential.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/pharmacology , Flow Cytometry , Glucose/analogs & derivatives , Glucose/pharmacology , Humans , Ifosfamide/analogs & derivatives , Ifosfamide/pharmacology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Membrane Potential, Mitochondrial/drug effects , Necrosis , Phosphoramide Mustards/pharmacology , Tumor Cells, Cultured
5.
Article in English | WPRIM | ID: wpr-149765

ABSTRACT

Triptolide, a compound extracted from the traditional Chinese medicine preparation of Tripterygium wilfordii Hook F., has been reported to have anti-inflammatory and anti-cancer activities. However, its effect on ovarian cancer invasion is unknown. We observed that MMP7 and MMP19 expression increased in ovarian cancer tissue. Triptolide treatment inhibited the migration and invasion of ovarian cancer cells SKOV3 and A2780 at the concentration of 15 nM. We also observed that triptolide suppressed MMP7 and MMP19 promoter activity in a dose-dependent manner, down-regulating the expressions of these promoters on mRNA and protein level. Moreover, triptolide enhanced E-cadherin expression in ovarian cancer cells. In vivo, triptolide inhibited tumor formation and metastasis in nude mice, and suppressed MMP7 and MMP19 expression; it also enhanced E-cadherin expression in tumor in a dose-dependent manner. Over expression of MMP7 and MMP19, or suppression of E-cadherin expression partially abolished the inhibitory effect of triptolide on invasion of ovarian cancer cells. To summarize, triptolide significantly inhibited the migration and invasion of ovarian cancer cells by suppression of MMP7 and MMP19 and up-regulation of E-cadherin expression. This study shows that triptolide is a good candidate for the treatment of ovarian cancer and reduction of metastasis.


Subject(s)
Animals , Antineoplastic Agents, Alkylating/pharmacology , Cadherins/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cystadenocarcinoma, Serous/drug therapy , Diterpenes/pharmacology , Epoxy Compounds/pharmacology , Female , Gene Expression Regulation, Enzymologic/drug effects , Humans , Matrix Metalloproteinase 7/genetics , Matrix Metalloproteinases, Secreted/genetics , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Ovarian Neoplasms/drug therapy , Paclitaxel/pharmacology , Phenanthrenes/pharmacology , Promoter Regions, Genetic , Up-Regulation/drug effects , Xenograft Model Antitumor Assays
6.
Article in English | WPRIM | ID: wpr-76424

ABSTRACT

In spite of the importance of phospholipase D (PLD) in cell proliferation and tumorigenesis, little is known about the molecules regulating PLD expression. Thus, identification of small molecules inhibiting PLD expression would be an important advance for PLD-mediated physiology. We examined one such here, denoted "Triptolide", which was identified in a chemical screen for inhibitors of PLD expression using cell assay system based on measurement of PLD promoter activity. Triptolide significantly suppressed the expression of both PLD1 and PLD2 with sub-microM potency in MDA-MB-231 breast cancer cells as analyzed by promoter assay and RT-PCR. Moreover, triptolide abolished the protein level of PLD in a time and dose-dependent manner. Triptolide-induced PLD1 downregulation was also observed in all the cancer cells examined, suggesting a general phenomenon detected in various cancer cells. Decrease of PLD expression by triptolide suppressed both basal and PMA-induced PLD activity. In addition, triptolide inhibited activation of NFkappaB which increased PLD1 expression. Ultimately, downregulation of PLD by triptolide inhibited proliferation of breast cancer cells. Taken together, we demonstrate that triptolide suppresses the expression of PLD via inhibition of NFkappaB activation and then decreases cell proliferation.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Diterpenes/pharmacology , Epoxy Compounds/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , NF-kappa B/genetics , Phenanthrenes/pharmacology , Phospholipase D/genetics
7.
Article in English | IMSEAR | ID: sea-17089

ABSTRACT

BACKGROUND & OBJECTIVE: Temozolomide (TMZ), a second generation alkylating drug, an effective cytotoxic agent as well as radiosensitizer for malignant brain tumours, has side effects like myelosuppression. Lonidamine (LND) increases the effectiveness of several experimental multiple chemotherapy protocols, without increasing bone marrow toxicities and is effective in brain tumour patients. The objective of the present studies was to investigate whether combining clinically relevant doses of LND and TMZ could increase the proliferation and radiation response of malignant human brain tumour cells in vitro. METHODS: A malignant human glioma (U373MG) cell line was used in these studies. TMZ (20, 40 or 60 microM) or LND (100, 150 or 200 microM), or the combination of both (20 and 100 microM, respectively) in 0.1 per cent dimethyl sulphoxide (DMSO) were added three days after setting up cultures, in six well plates (5 x 10(4) cells/ well). The effects of continuous treatment for two days on proliferation response and cytotoxicity were studied after trypsinization; by cell counts and the uptake of trypan blue dye (0.5%). For the study of radiation (60Co-Gamma-rays, 2 Gy) response, drugs were removed 4 h after irradiation and cultures were grown further in drug free, normal growth medium for another 20 h or 44 h. RESULTS: Continuous presence of TMZ or LND for two days significantly inhibited cell proliferation in a concentration dependent manner. The frequencies of non viable cells increased significantly only at higher concentrations of LND. Combination of 20 microM TMZ with 100 microM LND had additive effects on proliferation response, without affecting cell viability. Short-term drug treatments without irradiation did not induce micronuclei formation. Cell proliferation and viability were also not affected. However, post-irradiation presence of either of these drugs for 4 h significantly reduced the proliferation response, 24 and 48 h after treatments. It was further inhibited by the combination treatment. On the contrary, radiation induced micronuclei formation was enhanced by either of the drugs; which was significantly increased by the combined treatment, 24 h as well as 48 h after irradiation. No effects on cell viability were observed, immediately after these treatments as well as at later time points. INTERPRETATION & CONCLUSION: Our findings showed that combination of TMZ and LND at clinically achievable, low plasma concentrations could inhibit tumour growth, and lonidamine could reduce the dose of temozolomide required for radiosensitization of brain tumours.


Subject(s)
Acridine Orange , Analysis of Variance , Antineoplastic Agents, Alkylating/pharmacology , Brain Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Dacarbazine/analogs & derivatives , Gamma Rays , Humans , Indazoles/pharmacology , Radiation-Sensitizing Agents/pharmacology , Radiotherapy/methods
9.
Rev. bras. cancerol ; 48(3): 439-445, jul.-set. 2002.
Article in Portuguese | LILACS | ID: lil-427335

ABSTRACT

A temozolamida (TMZ) pertence a uma nova classe de agentes alquilantes, como um derivado da imidazotetrazina.A TMZ é uma substância de baixo peso molecular, sendo 100 por cento absorvida por via oral, e praticamente toda ela deverá ter sido eliminada após 8 horas da ingestão. Devido a esta rápida eliminação e ao seu mecanismo de ação, a TMZ tem risco reduzido de ser tóxica para a medula óssea. Por outro lado, em sendo uma substância lipofílica, a TMZ atravessa a barreira hemo-encefálica, o que a faz alcançar tumores cerebrais. Este medicamento apresenta atividade contra alguns tumores sólidos e tem sido investigada para tratamento de gliomas de alto grau, incluindo o Astrocitoma anaplásico (AA), o Glioblastomamultiforme (GBM), gliomas de baixo grau e o Melanoma maligno metastático (MM). Com a presente revisão bibliográfica, evidenciou-se ausência de bases técnicas e científicas que permitam considerar o TMZ um tratamento padrão dos tumores cerebrais ou do melanoma maligno metastático.


Subject(s)
Male , Female , Humans , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms , Drug Evaluation
10.
Indian J Exp Biol ; 1996 Jun; 34(6): 502-7
Article in English | IMSEAR | ID: sea-55713

ABSTRACT

To investigate the induction of adaptive response (inducible protective processes) in mitotic cells of Swiss albino mouse, a monofunctional alkylating agent methyl methanesulfonate (MMS) was employed. When the animals treated with a low dose of 50 mg/kg body weight were challenged with a subsequent high (challenging) dose of 150 mg/kg body weight, after different time lags (2,5,8 or 10 hr), the yield of chromosomal aberrations in bone marrow cells was found to be significantly reduced compared to the additive effects of both conditioning and challenging doses. It seems, therefore, that the low dose of MMS employed has made the cells less sensitive against further clastogenic effect of challenge dose of MMS. The data clearly suggest that the phenomenon of adaptive response to methylating agents can be encountered in in vivo mammalian cells. Furthermore, it is also observed that ethylating agent EMS is a poor inducer of adaptive response than its corresponding methylating agent MMS in the bone marrow cells of mouse.


Subject(s)
Adaptation, Physiological , Animals , Antineoplastic Agents, Alkylating/pharmacology , Bone Marrow/drug effects , Bone Marrow Cells , Dose-Response Relationship, Drug , Male , Methyl Methanesulfonate/pharmacology , Mice
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