Malignant gliomas are very difficult neoplasms for clinicians to treat. The reason for this is multifaceted. Many treatments that are effective for systemic cancer are unable to cross the blood-brain barrier and/or have unacceptable systemic toxicities. Consequently, in recent years an effort has been placed on trying to develop innovative local treatments that bypass the blood-brain barrier and allow for direct treatment in the central nervous system (CNS)-interstitial treatment. In this paper, we present our extensive experience in using interstitial chemotherapy as a strategy to treat malignant brain tumors at a single institution (The Johns Hopkins Hospital). We provide a comprehensive summary of our preclinical work on interstitial chemotherapy at the Hunterian Neurosurgery Laboratory, reviewing data on rat, rabbit, and monkey studies. Additionally, we present our clinical experience with randomized placebo-controlled studies for the treatment of malignant gliomas. We compare survival statistics for those patients who received placebo versus Gliadel as initial therapy (11.6 months vs. 13.9 months, respectively) and at the time of tumor recurrence (23 weeks vs. and 31 weeks, respectively). We also discuss the positive impact of local therapy in avoiding the toxicities associated with systemic treatments. Furthermore, we provide an overview of newer chemotherapeutic agents and other strategies used in interstitial treatment. Finally, we offer insight into some of the lessons we have learned from our unique perspective.
"Glioblastomas (GBMs) are the most aggressive brain tumors in humans and have the worst prognoses, with a median survival time of approximately 14 months and are almost invariably fatal1. Due to the resistance of tumor cells to conventional therapies, it is very difficult to treat GBMs234; however, the identification of genes or proteins that effectively inhibit tumor growth is expected to break through this bottleneck5. Our previous study revealed that dendritic cell factor (dcf1), also known as tmem59, was involved in differentiation of neural stem cells (NSCs)6, since dcf1 silencing tends to differentiate NSCs into astrocytes78. "
[Show abstract][Hide abstract] ABSTRACT: Gliomas are the most common brain tumors affecting the central nervous system and are associated with a high mortality rate. DCF1 is a membrane protein that was previously found to play a role in neural stem cell differentiation. In the present study, we found that overexpression of dcf1 significantly inhibited cell proliferation, migration, and invasion and dramatically promoted apoptosis in the glioblastoma U251 cell line. DCF1 deletion mutations in the functional region showed that the complete structure of DCF1 was necessary for apoptosis. Furthermore, significantly lower tumorigenicity was observed in athymic nude mice by transplanting U251 cells overexpressing dcf1. To decode the apoptosis induced by dcf1, mitochondrial structure and membrane potential in glioma cells were investigated and the results indicated obvious mitochondrial swelling, destruction of cristae, and a significant decline in membrane potential. Mechanismly, caspase-3 signaling was activated. Finally, endogenous dcf1 silence in U251 cells was investigated. Results showed a highly methylation at -1339 and -1322 position at dcf1 promoter sequence, revealing the causal relationship between dcf1 gene and tumorigencicity. The present study identified a previously unknown cancer apoptosis mechanism involving dcf1 overexpression and provided a novel approach to potentially treat glioma patients.
"Glioblastoma is an aggressive malignant primary brain tumor derived from glial cells and most commonly occurs in male without obvious genetic predisposition . The pathogenesis of glioblastoma remains obscure, and it is very difficult to treat because the tumor cells are resistant to conventional therapy and the blood-brain barrier blocks the entry of many drugs . "
[Show abstract][Hide abstract] ABSTRACT: 1,1-Dimethyl-4-phenyl piperazine iodide (DMPP) is an synthetic nicotinic acetylcholine receptor (nAChR) agonist that could reduce airway inflammation. In this study, we demonstrated that DMPP could dramatically inhibit glioma size maintained on chick embryonic chorioallantoic membrane (CAM). We first performed MTT and BrdU incorporation experiments on U87 glioma cells in vitro to understand the mechanism involved. We established that DMPP did not significant affect U87 cell proliferation and survival. We speculated that DMPP directly caused the tumor to regress by affecting the vasculature in and around the implanted tumor on our chick CAM model. Hence, we conducted detail analysis of DMPP's inhibitory effects on angiogenesis. Three vasculogenesis and angiogenesis in vivo models were used in the study which included (1) early chick blood islands formation, (2) chick yolk-sac membrane (YSW) and (3) CAM models. The results revealed that DMPP directly suppressed all developmental stages involved in vasculogenesis and angiogenesis - possibly by acting through Ang-1 and HIF-2α signaling. In sum, our results show that DMPP could induce glioma regression grown on CAM by inhibiting vasculogenesis and angiogenesis.
Experimental Cell Research 10/2013; 320(2). DOI:10.1016/j.yexcr.2013.10.009 · 3.25 Impact Factor
"Additionally, the high-dose corticosteroid therapy required with Gliadel® can also impair wound healing and increase infectious complications. A further limitation of Gliadel is that it cannot be implanted into patients with large ventricular openings due to the potential for dislodgement and subsequent obstructive hydrocephalus (Lawson et al. 2007)—this is significant since it is not uncommon for large malignant gliomas to abut the ventricular surface. As experience with the Gliadel wafer increases, complication rates appear to be decreasing (Attenello et al. 2008). "
[Show abstract][Hide abstract] ABSTRACT: Direct delivery of chemotherapy agents to the brain via degradable polymer delivery systems-such as Gliadel®-is a clinically proven method for treatment of glioblastoma multiforme, but there are important limitations with the current technology-including the requirement for surgery, profound local tissue toxicity, and limitations in diffusional penetration of agents-that limit its application and effectiveness. Here, we demonstrate another technique for direct, controlled delivery of chemotherapy to the brain that provides therapeutic benefit with fewer limitations. In our new approach, camptothecin (CPT)-loaded poly(lacticco-glycolic acid) (PLGA) nanoparticles are infused via convection-enhanced delivery (CED) to a stereotactically defined location in the brain, allowing simultaneous control of location, spread, and duration of drug release. To test this approach, CPT-PLGA nanoparticles (~100 nm in diameter) were synthesized with 25% drug loading. When these nanoparticles were incubated in culture with 9L gliosarcoma cells, the IC50 of CPT-PLGA nanoparticles was 0.04 µM, compared to 0.3 µM for CPT alone. CPT-PLGA nanoparticles stereotactically delivered by CED improved survival in rats with intracranial 9L tumors: the median survival for rats treated with CPT-PLGA nanoparticles (22 days) was significantly longer than unloaded nanoparticles (15 days) and free CPT infusion (17 days). CPT-PLGA nanoparticle treatment also produced significantly more long-term survivors (30% of animals were free of disease at 60 days) than any other treatment. CPT was present in tissues harvested up to 53 days post-infusion, indicating prolonged residence at the local site of administration. These are the first results to demonstrate the effectiveness of combining polymer-controlled release nanoparticles with CED in treating fatal intracranial tumors.
Drug Delivery and Translational Research 02/2011; 1(1):34-42. DOI:10.1007/s13346-010-0001-3
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