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- Delwar, Zahid M., et al.
(författare)
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Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells
- 2012
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Ingår i: Investigational New Drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 30:4, s. 1302-1310
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.05MG human glioma cells. A stronger antiproliferative effect was observed in the short-term proliferation assay with the M:SO combination compared to either investigated agent alone. In the long-term proliferation assay, a 10-day exposure to M:SO at concentrations of 10 mu M:17.5 mu M or 17.5 mu M:10 mu M was enough to kill 100% of the cells; no cell regrowth was observed after re-incubation in drug-free media. When used in combination, the single concentration of M and SO could be decreased by 2.5- to 5-fold of those used for each experimental drug alone and still obtain a similar antiproliferative effect. The underlying molecular mechanism was investigated by co-incubating M:SO with dithiothreitol (DTT) and genistein. Both substances partially neutralized the effects of the M:SO combination, showing additive effects. This observation suggests a role of oxidative stress and tyrosine kinase stimulation in the M:SO cytotoxic effect. Our results indicate that M:SO combination is an attractive alternative for glioma treatment that encourages further study. The neutralizing effects of genistein and DTT reveal a possibility for their use in the minimization of potential M:SO systemic toxicity.
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| 2. |
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| 3. |
- Vita, Marina F., et al.
(författare)
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Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C
- 2011
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Ingår i: Investigational New Drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 29:6, s. 1314-1320
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Tidskriftsartikel (refereegranskat)abstract
- Menadione (Vitamin K3) has anti-tumoral effects against a wide range of cancer cells. Its potential toxicity to normal cells and narrow therapeutic range limit its use as single agent but in combination with radiation or other anti-neoplastic agents can be of therapeutic use. In this paper, we first evaluated the early (within 3 h) effect of menadione on ongoing DNA replication. In normal rat cerebral cortex mini-units menadione showed an age dependent anti-proliferative effect. In tissue mini-units prepared from newborn rats, menadione inhibited ongoing DNA replication with an IC (50) of approximately 10 mu M but 50 mu M had no effect on mini-units from prepared adult rat tissue. The effect of short (72 h) and prolonged exposure (1-2 weeks) to menadione alone in the DBTRG.05MG human glioma cells line and in combination with vitamin C was studied. After short period of exposure data show that menadione alone or in combination with vitamin C provided similar concentration-response curves (and IC50 values). Prolonged exposure to these drugs was evaluated by their ability to kill 100% of glioma cells and prevent regrowth when cells are re-incubated in drug-free media. In this long-term assay, menadione:vitamin C at a ratio 1:100 showed higher anti-proliferative activity when compared to each drug alone and allowed to reduce each drug concentration between 2.5 to 5-fold. Similar anti-proliferative effect was demonstrated in 8 patient derived glioblastoma cell cultures. Our data should be able to encourage further advanced studies on animal models to evaluate the potential use of this combination therapy for glioma treatment.
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| 4. |
- Yakisich, Juan Sebastián
(författare)
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Regulation of ongoing DNA synthesis in normal and neoplastic brain tissue
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The treatment of human brain tumour is challenging in part due to the blood brain barrier and in part due to the specific biology of brain tumours that confer resistance to chemotherapy. For instance, the 5 years survival rate for patients carrying intracranial glioblastoma multiforme has remained at 4-5 % for the last 30 years. The knowledge of the brain tumour biology as well as the biology of the normal brain tissue would help to design new therapeutic strategies and to develop new and less toxic antineoplastic drugs for brain tumour treatment. Normal tissue must be studied in order to identify tumour-specific vulnerabilities and ways to inhibit toxicity in the host. The present thesis describes a series of investigations of potential antineoplastic drugs performed in normal rat cerebral cortex, human brain tumour specimens and RG2 gliomas, performed "in vitro" in order to 1) better understand factors controlling the cell cycle and DNA replication in normal and neoplastic brain tissue, and thus, exploiting potential targets for new drugs 2) better apply the available antineoplastic drugs for the treatment of human brain tumours while producing no or low side effect on normal tissue. A novel assay, which preserves the metabolic and proliferative properties of the tissue was developed and used to study ongoing DNA synthesis and its regulation by protein phosphorylation and proteolysis. The effect of low MW drugs (protein kinase and protease inhibitors) on these processes was evaluated, By analyzing the effects of different chemically unrelated inhibitors of protein kinases we found that many of these inhibitors might act through long term mechanism of action (e.g. inhibiting cell cycle transitions) rather than a direct effect on the DNA replication machinery, although some of these drugs are currently used as "DNA synthesis inhibitors". We suggest that, from the clinical point of view, it would be important to distinguish between these long and short-term mechanism of action. Our results also suggest that different sets of protein kinases and proteases yet not clearly identified regulate "ongoing DNA replication". A more detailed study was carried out using roscovitine, a highly specific cyclin-dependent kinase inhibitor. The effect of roscovitine on DNA synthesis was evaluated in normal rat cerebral cortex, specimens obtained from human brain tumours and in a pilot experiment using a rat glioma model. We found that roscovitine is a potent inhibitor of ongoing DNA synthesis in the developing rat cerebral cortex as well as in human gliomas but showed little or no effect in adult normal tissue. Moreover, roscovitine inhibited preferentially DNA synthesis connected with replicative processes rather than DNA synthesis connected with DNA repair. In addition, some in vitro studies of redox regulation of topoisomerases and the effects of thiol reacting drugs on this enzyme are presented.
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