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sensitized the cells to cisplatin-induced apoptosis. Furthermore, adenovirus E1a increases sensitivity to cisplatin by blocking AKT activation . Finally, AKT can cause an increase in NF-kB which leads to decreased apoptosis and cisplatin resistance . While studies of this type have not yet been done in gliomas, investigations of PTEN inactivation in these tumors and design of new therapies targeting AKT and other signal transduction pathways are ongoing and are likely to lead to new methodologies to reduce resistance to cisplatin in brain tumors. To date, most studies in brain tumors have centered on DNA repair.
In addition to the alkylating agents, the topoisome-rase inhibitors are being used in the treatment of some gliomas. CPT-11 (irinotecan), an inhibitor of topoisomerase I has shown efficacy against gliomas, particularly in combination with BCNU or temozolo-mide [26-30]. This prodrug crosses the blood-brain barrier, is converted by carboxylesterases to its active metabolite SN-38 which then interacts directly with topoisomerase I, stabilizing covalent topo I-DNA complexes and forming single strand DNA breaks . Resistance to this drug may come about through a point mutation in topoisomerase I resulting in an enzyme with reduced activity or reduced expression of the enzyme [32,33] or through increased efflux of the drug mediated by the ATP-binding cassette system .
Etoposide (VP-16), an inhibitor of topoisomerase II was originally thought to inhibit microtubules. It is now known that this drug acts by stabilizing the cleavable complex that is formed when topoisomerase II interacts with the DNA, cuts both strands of DNA and forms covalent bonds with the ends. This complex is normally short-lived and the DNA breaks are resealed afer the DNA goes through rotation or strand passage. In the presence of etoposide the DNA strands cannot rotate, resulting in a persistent cleavable complex and DNA strand breaks [34,35]. Clinical trials have included VP-16 with a variety of other compounds in the treatment of both pediatric and adult brain tumors [35-45], and the main mechanism of resistance is thought to be related to increased efflux via ATP-binding cassette proteins including the multidrug-resistant-associated protein (MRP) [46,47].
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