Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylase (HDAC) inhibitors represent a promising class of anti-cancer agents that are actively being evaluated in the context of clinical trials in solid tumors, including glioblastoma. What makes these agents particularly attractive is their capacity to enhance the activity of commonly used cytotoxics in cancer therapy, including both chemotherapy and ionizing radiation. As recent investigations suggest HDAC inhibitors may potentiate the cytotoxicity of topoisomerase inhibitors, which continue to be a commonly used class of agents in the treatment of glioblastoma, we performed preclinical studies to determine if this combination may be a promising strategy in glioblastoma. The effects of the HDAC inhibitor vorinostat and SN38, which is the active metabolite of the topoisomerase I inhibitor CPT-11, was evaluated using the clonogenic assay. Various treatment schedules were tested to determine optimum drug sequencing. Induction of DNA double strand breaks (DSBs) with the combination of vorinostat and SN38 was evaluated using the neutral comet assay, and their subsequent repair was evaluated by gammaH2AX foci kinetics using immunofluorescent cytochemistry. Vorinostat enhanced the cytotoxicity of SN38 in glioblastoma cell lines. Optimal treatment schedules involved maximal concurrent administration of agents. Pretreatment with either agent did not enhance cytotoxicity. Vorinostat potentiated SN38-induced DNA DSBs and attenuated their subsequent repair. These results indicate vorinostat enhances the cytotoxicity of SN38 in glioblastoma cell lines, suggesting this combination may be a worthwhile strategy to test in the context of a clinical trial.
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PMID:Vorinostat enhances the cytotoxic effects of the topoisomerase I inhibitor SN38 in glioblastoma cell lines. 2013 94

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.
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PMID:Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma. 2202 88

Glioblastoma (GBM), the most common primary brain tumor in adults, is usually rapidly fatal with median survival duration of only 15 months and a 3-year survival rate of <7 %. Temozolomide (TMZ) is the only anticancer drug that has improved survival in GBM when administered with concomitant radiotherapy. Irinotecan (CPT-11) has also shown efficacy in recurrent gliomas monotherapy with moderate response. As the efficacy of GBM treatments relies on their brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study, on an in vivo model, the brain distribution of TMZ, CPT-11 and its active metabolite, SN-38. We have focussed on the role of ABCB1, the main efflux transporter at the BBB level, through pharmacokinetics studies in CF1 mdr1a(+/+) and mdr1a(-/-) mice. Our results show that TMZ, CPT-11 and SN-38 are transported by ABCB1 at the BBB level with brain/plasma ratios of 1.1, 2.1 and 2.3, respectively.
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PMID:Irinotecan and temozolomide brain distribution: a focus on ABCB1. 2486 82

OBJECT Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution. METHODS Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels. RESULTS The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV-treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV-treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice. CONCLUSIONS The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas.
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PMID:Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals. 2572 30

An intestine-liver-glioblastoma biomimetic system was developed to evaluate the drug combination therapy for glioblastoma. A hollow fiber (HF) was embedded into the upper layer of the microfluidic chip for culturing Caco-2 cells to mimic drug delivery as an artificial intestine. HepG2 cells cultured in the bottom chamber of the chip acted as an artificial liver for metabolizing the drugs. The dual-drug combination to glioblastoma U251 cells was evaluated based on the intestine-liver metabolic model. The drugs, irinotecan (CPT-11), temozolomide (TMZ) and cyclophosphamide (CP), were used to dynamically stimulate the cells by continuous infusion into the intestine unit. After intestine absorption and liver metabolism, the prodrugs were transformed to active metabolites, which induced glioblastoma cells apoptosis. The anticancer activity of the CPT-11 and TMZ combination is significantly enhanced compared to that of the single drug treatments. Combination index (CI) values of the combination groups, CPT-11 and TMZ, CPT-11 and CP, and TMZ and CP, at half maximal inhibitory concentration were 0.137, 0.288, and 0.482, respectively. The results indicated that the CPT-11 and TMZ combination was superior to the CPT-11 and CP group as well as the TMZ and CP group towards the U251 cells. The metabolism mechanism of CPT-11 and TMZ was further studied by coupling with mass spectrometric analysis. The biomimetic model enables the performance of long-term cell co-culture, drug delivery, metabolism and real-time analysis of drug effects, promising systematic in vitro mimicking of physiological and pharmacological processes.
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PMID:Evaluation of drug combination for glioblastoma based on an intestine-liver metabolic model on microchip. 2885 86

In this study, we aimed to develop a multifunctional drug/gene delivery system for the treatment of glioblastoma multiforme by combining the ligand-mediated active targeting and the pH-triggered drug release features of graphene oxide (GO). Toward this end, we load irinotecan (CPT-11) to cetuximab (CET)-conjugated GO (GO-CET/CPT11) for pH-responsive drug release after endocytosis by epidermal growth factor receptor (EGFR) over-expressed U87 human glioblastoma cells. The ultimate injectable drug/gene delivery system was designed by co-entrapping stomatin-like protein 2 (SLP2) short hairpin RNA (shRNA) and GO-CET/CPT11 in thermosensitive chitosan-g-poly(N-isopropylacrylamide) (CPN) polymer solution, which offers a hydrogel depot for localized, sustained delivery of the therapeutics after the in situ formation of CPN@GO-CET/CPT11@shRNA hydrogel. An optimal drug formulation was achieved by considering both the loading efficiency and loading content of CPT-11 on GO-CET. A sustained and controlled release behavior was found for CPT-11 and shRNA from CPN hydrogel. Confocal microscopy analysis confirmed the intracellular trafficking for the targeted delivery of CPT-11 through interactions of CET with EGFR on the U87 cell surface. The efficient transfection of U87 using SLP2 shRNA was achieved using CPN as a delivery milieu, possibly by the formation of shRNA/CPN polyplex after hydrogel degradation. In vitro cell culture experiments confirmed cell apoptosis induced by CPT-11 released from acid organelles in the cytoplasm by flow cytometry, as well as reduced SLP2 protein expression and inhibited cell migration due to gene silencing. Finally, in vivo therapeutic efficacy was demonstrated using the xenograft of U87 tumor-bearing nude mice through non-invasive intratumoral delivery of CPN@GO-CET/CPT11@shRNA by injection. Overall, we have demonstrated the novelty of this thermosensitive hydrogel to be an excellent depot for the co-delivery of anticancer drugs and siRNA. The in situ forming hydrogel will not only provide extended drug release but also combine the advantages offered by the chitosan-based copolymer structure for siRNA delivery to broaden treatment modalities in cancer therapy.
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PMID:Injectable Thermo-Sensitive Chitosan Hydrogel Containing CPT-11-Loaded EGFR-Targeted Graphene Oxide and SLP2 shRNA for Localized Drug/Gene Delivery in Glioblastoma Therapy. 3299 66

Zinc(II)-dipicolylamine (Zn-DPA) has been shown to specifically identify and bind to phosphatidylserine (PS), which exists in bulk in the tumor microenvironment. BPRDP056, a Zn-DPA-SN38 conjugate was designed to provide PS-targeted drug delivery of a cytotoxic SN38 to the tumor microenvironment, thereby allowing a lower dosage of SN38 that induces apoptosis in cancer cells. Micro-Western assay showed that BPRDP056 exhibited apoptotic signal levels similar to those of CPT-11 in the treated tumors growing in mice. Pharmacokinetic study showed that BPRDP056 has excellent systemic stability in circulation in mice and rats. BPRDP056 is accumulated in tumors and thus increases the cytotoxic effects of SN38. The in vivo antitumor activities of BPRDP056 have been shown to be significant in subcutaneous pancreas, prostate, colon, liver, breast, and glioblastoma tumors, included an orthotopic pancreatic tumor, in mice. BPRDP056 shrunk tumors at a lower (~20% only) dosing intensity of SN38 compared to that of SN38 conjugated in CPT-11 in all tumor models tested. A wide spectrum of antitumor activities is expected to treat all cancer types of PS-rich tumor microenvironments. BPRDP056 is a first-in-class small molecule drug conjugate for cancer therapy.
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PMID:BPRDP056, a novel small molecule drug conjugate specifically targeting phosphatidylserine for cancer therapy. 3306 1


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