Transforming growth factor-β (TGF-β) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis,
and immunosuppression. Antisense oligonucleotide suppression of TGF-β 2 ...ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-β
in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-β receptor,
on a panel of human malignant glioma cell lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs,
intracellular mediators of TGF-β signaling, with decreased TGF-β–mediated transcription. Furthermore, SB-431542 inhibited
the expression of two critical effectors of TGF-β-vascular endothelial growth factor and plasminogen activator inhibitor-1.
SB-431542 treatment of glioma cultures inhibited proliferation, TGF-β–mediated morphologic changes, and cellular motility.
Together, our results suggest that small molecule inhibitors of TGF-β receptors may offer a novel therapy for malignant gliomas
by reducing cell proliferation, angiogenesis, and motility.
Purpose: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms
that underlie their formation and maintenance. CNS tumors depend ...on angiogenesis and often display increased activity of ErbB-associated
pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing
need for the development of novel targeted therapies.
Experimental Design: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial
growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment
of several CNS tumor types.
Results: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a
limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in
most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation
of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably,
some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth
factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal
growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control.
Conclusions: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration
for clinical development in this disease setting seems warranted.
A 34-year-old man presented with progressive visual loss, diplopia, headache, intermittent fever, and significant weight loss for 7 months. Physical examination revealed bilateral visual loss and ...exophthalmos with complete ophthalmoplegia. Imaging demonstrated pachymeningeal enhancement, soft tissue infiltration in the retro-orbital spaces and multiple organs including kidneys and abdominal aorta, and mixed osteosclerotic and osteolytic lesions in bilateral femoral heads1 (figure). Pathologic study of the retro-orbital lesion revealed foamy histiocytes negative for CD1a and S100,2 consistent with Erdheim-Chester disease (ECD). The patient was treated with IV methylprednisolone followed by cyclosporine with minimal benefit. Four months later, he died due to sudden unexplained death during sleep. An autopsy was not performed. ECD is a rare, non-Langerhans histiocytosis characterized by chronic histiocytic infiltration of multiple organs. Common manifestations include bone pain, diabetes insipidus, exophthalmos, and xanthelasma.1 The nervous system is affected in 25%-50% of patients and can be involved in the extra-axial and intra-axial compartments.1,2 Standard treatment has not been established.
Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. ...Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.
•distinct patterns of cytokine levels between SCAR and non-SCAR PBMCs in epilepsy.•DRESS PBMCs produced different patterns of cytokine as compared to SJS/TEN PBMCs.•IL-5 and IL-13 might be a ...promising marker to define drug hypersensitivity in DRESS.
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reactions with eosinophilia and systemic symptoms (DRESS) are the most common severe cutaneous adverse drug reactions (SCARs). Anti-epileptic drugs are one of the most common drugs causing SCARs. Cytokine profiles of SCARs during culprit drug exposure have never been characterized. This study aimed to identify cytokine patterns between SCARs and non-SCARs in epilepsy patients and the patterns of DRESS and SJS/TEN. Epilepsy patients that showed allergic responses to anti-epileptic drugs that manifested as SJS/TEN or DRESS were recruited. Epilepsy patients with no drug allergy symptoms and healthy people were also recruited as control groups. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with assigned anti-epileptic drugs according to the lymphocyte transformation test (LTT). LTT and measurement of cytokine levels in supernatants were performed on day six of cell cultivation. This study identified different cytokine expression patterns between SCAR and non-SCAR in epilepsy patients. Significant levels of IL-10, IL-12, IL-17, and GM-CSF were detected in non-SCAR epilepsy. However, the levels of IL-2, IL-5, IL-13, and IFN-gamma were significantly higher in supernatants of PBMCs of DRESS cultivated with AEDs relative to those of SJS/TEN. These cytokine levels were positively correlated with the cell proliferation index. Production of IL-5 and IL-13 was a unique characteristic of DRESS PBMCs. This study was the first to demonstrate distinct differences in cytokine levels between SCAR and non-SCAR PBMCs in epilepsy, which could help explain the immune-pathomechanism of drug hypersensitivity in SCARs. Different patterns of cytokine production and cell proliferation between DRESS and SJS/TEN in AED hypersensitivity were also demonstrated. Production of IL-5 and IL-13 might be a promising marker to define drug hypersensitivity in DRESS.
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•PLGA (core)/liposome (shell) nanoparticle was developed for cisplatin targeting delivery.•Physicochemical, encapsulation efficiency and drug release profiles were characterized.•This ...study confirmed that L-PLGA-Cis-Avastin® had binding specificity to SiHa cells.•Tumor targeting specificity was finally confirmed in xenograft tumors.
Cisplatin (Cis) is a widely used chemotherapeutic drug for cancer treatment. However, toxicities and drug resistance limit the use of cisplatin. This study was aimed to improve cisplatin delivery using a targeting strategy to reduce the toxicity. In the present study, combinations of poly lactic-co-glycolic acids (PLGA) and liposomes were used as carriers for cisplatin delivery. In addition, to target the nanoparticle towards tumor cells, the liposome was conjugated with Avastin®, an anti-VEGF antibody. Cisplatin was loaded into PLGA using the double emulsion solvent evaporation method and further encapsulated in an Avastin® conjugated liposome (define herein as L-PLGA-Cis-Avastin®). Their physicochemical properties, including particle size, ζ-potential, encapsulation efficiency and drug release profiles were characterized. In addition, a study of the efficiency of tumor targeted drug delivery was conducted with cervical tumor bearing mice via intravenous injection. The therapeutic effect was examined in a 3D spheroid of SiHa cell line and SiHa cells bearing mice. The L-PLGA-Cis-Avastin® prompted a significant effect on cell viability and triggered cytotoxicity of SiHa cells. A cell internalization study confirmed that the L-PLGA-Cis-Avastin® had greater binding specificity to SiHa cells than those of L-PLGA-Cis or free drug, resulting in enhanced cellular uptake. Tumor targeting specificity was finally confirmed in xenograft tumors. Taken together, this nanoparticle could serve as a promising specific targeted drug for cervical cancer treatment.
Primary brain tumors account for less than 2% of all cancers in adults; however, they are often associated with neurologic morbidity and high mortality. Glioblastoma multiforme (GBM) has been a focus ...of new therapy development in neurooncology because it is the most common primary brain tumor in adults. Standard‐of‐care therapy for newly diagnosed GBM includes surgical resection, radiotherapy, and temozolomide, administered both during and after radiotherapy. However, most patients develop tumor recurrence or progression after this multimodality treatment. Repeat resection and stereotactic radiosurgery upon recurrence may improve outcome only in selected patients. Most salvage chemotherapies offer only palliation. Recent advances in our understanding of the molecular abnormalities of GBM have generated new therapeutic venues of molecularly targeted agents (designer drugs) against key components of cellular pathways critical for cancer initiation and maintenance. Such drugs may offer the potential advantage to increase therapeutic efficacy and decrease systemic toxicity compared with traditional cytotoxic agents. Nonetheless, first‐generation targeted agents have failed to demonstrate survival benefits in unselected GBM patient populations. Several mechanisms of treatment failure of the first‐generation designer drugs have been proposed, whereas new strategies have been developed to increase effectiveness of these agents. Here we will discuss the recent development and the strategies to optimize the effectiveness of designer therapy for GBM.
Glioblastoma, GBM, is a primary malignant brain tumor and is one of the most difficult-to-treat cancers. The inability of drugs to cross the blood brain barrier (BBB) is the main obstacle for ...treating brain cancers. The development of drug delivery systems which improve the permeation across the BBB is the focus of this research, specifically the benefits and use of nanostructured lipid carriers (NLC). The anti-inflammatory and anti-tumor activity of garlic oil have been widely studied. However, direct treatment with garlic oil is restricted due to its low bioavailability and the application of drug for brain cancer to improve the efficiency of garlic oil, a NLC was developed as a carrier of garlic oil. The garlic NLC was formulated using the hot high-pressure homogenization technique. The physicochemical properties of the garlic NLC were analyzed using dynamic light scattering. Size of the garlic NLC was 136.8 ± 0.56 nm and the zeta potentials of each formulation were −36.27 ± 0.96 mV and PDI 0.163 ± 0.03. The effect of garlic NLC on the cell viability of the glioma cell was determined using a MTT assay. The garlic NLC had higher efficiency towards inhibiting cell viability of glioma cells compared to free garlic oil. In addition, the effects of the garlic NLC on cell migration and cell invasion were assessed using a Boyden chamber assay. The migration and invasion abilities of garlic NLC treated cells were significantly decreased compared to the control and free garlic oil. Moreover, in vitro BBB was used to test permeation of garlic oil across BBB. Interestingly, garlic NLC could cross the BBB while the free garlic oil could not. Taken together, garlic NLC might be applicable as an alternative therapeutic treatment strategy for brain cancer.
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•The developed garlic NLC drastically improve the antitumor activity of garlic oil.•The garlic NLC inhibited cell viability of glioma cell via induction of apoptosis.•The garlic NLC could inhibit cell migration and cell invasion of glioma cells.•The garlic NLC improved the permeability of garlic oil to cross the blood brain barrier.
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