Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis.

Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation inhibitors have previously been shown to promote regulatory T cell responses and, in the present study, we evaluated their potential to ameliorate chronic and acute animal models of rheumatoid arthritis. Of the drugs tested, decitabine was the most effective, producing a sustained therapeutic effect that was dependent on indoleamine 2,3-dioxygenase (IDO) and was associated with expansion of induced regulatory T cells, particularly at the site of disease activity. Treatment with decitabine also caused apoptosis of Th1 and Th17 cells in active arthritis in a highly selective manner. The molecular basis for this selectivity was shown to be ENT1, a nucleoside transporter, which facilitates intracellular entry of the drug and is up-regulated on effector T cells during active arthritis. It was further shown that short-term treatment with decitabine resulted in the generation of a population of regulatory T cells that were able to suppress arthritis upon adoptive transfer. In summary, a therapeutic approach using an approved drug is described that treats active inflammatory disease effectively and generates robust regulatory T cells with the IDO-dependent capacity to maintain remission.

A glioma classification scheme based on coexpression modules of EGFR and PDGFRA.

We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM(low)PM(low) gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM(low)PM(low) gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM(low)PM(low) gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtype-specific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.

Calcium efflux of plasma membrane vesicles exposed to ELF magnetic fields--test of a nuclear magnetic resonance interaction model.

The question whether very weak, low frequency magnetic fields can affect biological matter is still under debate. The theoretical possibility of such an interaction is often questioned and the site of interaction in the cell is unknown. In the present study, the influence of extremely weak 60 Hz magnetic fields on the transport of Ca(2+) was studied in a biological system consisting of highly purified plasma membrane vesicles. We tested a newly proposed quantum mechanical model postulates that polarization of hydrogen nuclei can elicit a biological effect. Vesicles were exposed for half an hour at 32 °C and the calcium efflux was studied using radioactive (45) Ca(2+) as a tracer. A static magnetic field of 26 µT and time-varying magnetic fields with a frequency of 60 Hz and amplitudes between 0.6 and 6.3 µT were used. The predictions of the model, proposed by Lednev, that at a frequency of 60 Hz the biological effect under investigation would significantly be altered at the amplitudes of 1.3 and 3.9 µT could not be confirmed.

What is the role of CRP in glioblastoma?

BACKGROUND: Glioblastoma is the most common primary malignant brain tumor in adults. Previous studies have suggested that CRP (C-reactive protein) could serve as a biomarker candidate as well as a prognostic factor in glioblastoma patients, and we here further investigate its potential role. MATERIALS AND METHODS: Publicly available datasets were used to compare gene expression between brain samples from glioblastoma patients and non-tumor tissue. The structure of CRP was compared between humans and rats. Glioblastoma cells from humans and rats were stained with anti-CRP. Fischer 344 rats were inoculated with syngeneic glioblastoma cells pre-coated with anti-CRP, and survival was monitored. CRP concentration in rats carrying glioblastoma was followed. RESULTS: CRP was upregulated on one locus on gene level in glioblastoma tissue as compared to non-tumor brain tissue, but not in glioma stem cells as compared to neural stem cells. The structure of the CRP protein was a characteristic pentamer in both humans and rats. Both human and rat glioblastoma cells were clearly positive for anti-CRP staining. Pre-coating of glioblastoma cells with anti-CRP antibodies did not affect survival in rats with intracranial tumors. Serum levels of CRP increased during tumor progression but did not reach significantly different levels. CONCLUSIONS: Both human and rat glioblastoma cells could be stained with anti-CRP antibodies in vitro. In a syngeneic glioblastoma rat model we could see an increase in serum CRP during tumor progression, but coating glioblastoma cells with anti-CRP antibodies did not provide any survival change for the animals.

Distribution, cellular localization, and therapeutic potential of the tumor-associated antigen Ku70/80 in glioblastoma multiforme.

Antibodies specifically targeting tumor-associated antigens have proved to be important tools in the treatment of human cancer. A desirable target antigen should be unique to tumor cells, abundantly expressed, and readily available for antibody binding. The Ku70/80 DNA-repair protein is expressed in the nucleus of most cells; it is, however, also present on the cell surface of tumor cell lines, and antibodies binding Ku70/80 at the cell surface were recently shown to internalize into tumor cells. To evaluate the potential of Ku70/80-antigen as a therapeutic target for immunotoxins in glioblastoma multiforme, we investigated binding and localization of Ku70/80-specific antibodies in tissue samples from glioblastomas and normal human brains, and in glioma cell cultures. Furthermore, the internalization and drug-delivery capacity were evaluated by use of immunotoxicity studies. We demonstrate that Ku70/80 is localized on the cell plasma membrane of glioma cell lines, and is specifically present in human glioblastoma tissue. Antibodies bound to the Ku70/80 antigen on the cell surface of glioma cells were found to internalize via endocytosis, and shown to efficiently deliver toxins into glioblastoma cells. The data further imply that different antibodies directed against Ku70/80 possess different abilities to target the antigen, in relation to its presentation on the cell surface or intracellular localization. We conclude that Ku70/80 antigen is uniquely presented on the plasma membrane in glioblastomas, and that antibodies specific against the antigen have the capacity to selectively bind, internalize, and deliver toxins into tumor cells. These results imply that Ku70/80 is a potential target for immunotherapy of glioblastoma multiforme.

Growth pattern of experimental glioblastoma.

Glioblastoma multiforme (GBM) is an aggressive primary brain malignancy with a very poor prognosis. Researchers employ animal models to develop potential therapies. It is important that these models have clinical relevance. This means that old models, propagated for decades in cultures, should be questioned. Parameters to be evaluated include whether animals are immune competent or not, the infiltrative growth pattern of the tumor, tumor volume resulting in symptoms and growth rate. We here describe the growth pattern of an experimental glioblastoma model in detail with GFP positive glioblastoma cells in fully immune competent animals and study tumor growth rate and tumor mass as a function of time from inoculation. We were able to correlate findings made with classical immunohistochemistry and MR findings. The tumor growth rate was fitted by a Gompertz function. The model predicted the time until onset of symptoms for 5000 inoculated cells to 18.7±0.4 days, and the tumor mass at days 10 and 14, which are commonly used as the start of treatment in therapeutic studies, were 5.97±0.62 mg and 29.1±3.0 mg, respectively. We want to raise the question regarding the clinical relevance of the outline of glioblastoma experiments, where treatment is often initiated at a very early stage. The approach presented here could potentially be modified to gain information also from other tumor models.

Increased blood-brain barrier permeability in mammalian brain 7 days after exposure to the radiation from a GSM-900 mobile phone.

Microwaves were for the first time produced by humans in 1886 when radio waves were broadcasted and received. Until then microwaves had only existed as a part of the cosmic background radiation since the birth of universe. By the following utilization of microwaves in telegraph communication, radars, television and above all, in the modern mobile phone technology, mankind is today exposed to microwaves at a level up to 10(20) times the original background radiation since the birth of universe. Our group has earlier shown that the electromagnetic radiation emitted by mobile phones alters the permeability of the blood-brain barrier (BBB), resulting in albumin extravasation immediately and 14 days after 2h of exposure. In the background section of this report, we present a thorough review of the literature on the demonstrated effects (or lack of effects) of microwave exposure upon the BBB. Furthermore, we have continued our own studies by investigating the effects of GSM mobile phone radiation upon the blood-brain barrier permeability of rats 7 days after one occasion of 2h of exposure. Forty-eight rats were exposed in TEM-cells for 2h at non-thermal specific absorption rates (SARs) of 0mW/kg, 0.12mW/kg, 1.2mW/kg, 12mW/kg and 120mW/kg. Albumin extravasation over the BBB, neuronal albumin uptake and neuronal damage were assessed. Albumin extravasation was enhanced in the mobile phone exposed rats as compared to sham controls after this 7-day recovery period (Fisher's exact probability test, p=0.04 and Kruskal-Wallis, p=0.012), at the SAR-value of 12mW/kg (Mann-Whitney, p=0.007) and with a trend of increased albumin extravasation also at the SAR-values of 0.12mW/kg and 120mW/kg. There was a low, but significant correlation between the exposure level (SAR-value) and occurrence of focal albumin extravasation (r(s)=0.33; p=0.04). The present findings are in agreement with our earlier studies where we have seen increased BBB permeability immediately and 14 days after exposure. We here discuss the present findings as well as the previous results of altered BBB permeability from our and other laboratories.

Upregulation of C1-inhibitor in pancreatic cancer.

PURPOSE: The complement system has recently sparked more interest in cancer research. The classical pathway is initiated by activation of the C1 complex, which irreversibly can be bound to and inhibited by C1-INH. We have previously shown that C1-INH is upregulated in human glioblastoma (astrocytoma grade IV) on both gene and protein level. We here examine whether the complement system seems to play a role also in pancreatic cancer. TECHNIQUE AND RESULTS: We performed an expression analysis of complement associated genes in 36 pancreatic ductal adenocarcinoma tumors and matching normal pancreatic tissue samples from pancreatic cancer patients (data from the publicly available database GSE15471). C1-INH was significantly upregulated in the pancreatic cancer tissue. None of the downstream components of the cascade were significantly upregulated in the cancer samples as compared to the control samples, which is the same pattern as we found in glioblastoma. GO analysis showed that membrane attack complex came up as the second most significantly associated cellular component. Analyzing gene expression of C1-INH in the pancreatic cancer cell lines from primary tumors versus metastatic tumor revealed no difference for the two mRNA transcripts (GSE59357). INTERPRETATION: Analysis of gene expression of complement related genes shows an upregulation of C1-INH and a downregulation of downstream components. This could suggest that C1-INH plays a role also in pancreatic cancer.

Boron neutron capture therapy (BNCT) for glioblastoma multiforme: a phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA).

BACKGROUND AND PURPOSE: To evaluate the efficacy and safety of boron neutron capture therapy (BNCT) for glioblastoma multiforme (GBM) using a novel protocol for the boronophenylalanine-fructose (BPA-F) infusion. PATIENT AND METHODS: This phase II study included 30 patients, 26-69 years old, with a good performance status of which 27 have undergone debulking surgery. BPA-F (900 mg BPA/kg body weight) was given i.v. over 6h. Neutron irradiation started 2h after the completion of the infusion. Follow-up reports were monitored by an independent clinical research institute. RESULTS: The boron-blood concentration during irradiation was 15.2-33.7 microg/g. The average weighted absorbed dose to normal brain was 3.2-6.1 Gy (W). The minimum dose to the tumour volume ranged from 15.4 to 54.3 Gy (W). Seven patients suffered from seizures, 8 from skin/mucous problem, 5 patients were stricken by thromboembolism and 4 from abdominal disturbances in close relation to BNCT. Four patients displayed 9 episodes of grade 3-4 events (WHO). At the time for follow-up, minimum ten months, 23 out of the 29 evaluable patients were dead. The median time from BNCT treatment to tumour progression was 5.8 months and the median survival time after BNCT was 14.2 months. Following progression, 13 patients were given temozolomide, two patients were re-irradiated, and two were re-operated. Patients treated with temozolomide lived considerably longer (17.7 vs. 11.6 months). The quality of life analysis demonstrated a progressive deterioration after BNCT. CONCLUSION: Although, the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy and the treatment time is shorter, the observed side effects and the requirement of complex infrastructure and higher resources emphasize the need of further phase I and II studies, especially directed to improve the accumulation of (10)B in tumour cells.

Cognitive impairment in rats after long-term exposure to GSM-900 mobile phone radiation.

Considering the frequent use of mobile phones, we have directed attention to possible implications on cognitive functions. In this study we investigated in a rat model the long-term effects of protracted exposure to Global System for Mobile Communication-900 MHz (GSM-900) radiation. Out of a total of 56 rats, 32 were exposed for 2 h each week for 55 weeks to radio-frequency electromagnetic radiation at different SAR levels (0.6 and 60 mW/kg at the initiation of the experimental period) emitted by a (GSM-900) test phone. Sixteen animals were sham exposed and eight animals were cage controls, which never left the animal house. After this protracted exposure, GSM-900 exposed rats were compared to sham exposed controls. Effects on exploratory behaviour were evaluated in the open-field test, in which no difference was seen. Effects on cognitive functions were evaluated in the episodic-like memory test. In our study, GSM exposed rats had impaired memory for objects and their temporal order of presentation, compared to sham exposed controls (P = 0.02). Detecting the place in which an object was presented was not affected by GSM exposure. Our results suggest significantly reduced memory functions in rats after GSM microwave exposure (P = 0.02).

Blood-brain barrier permeability and nerve cell damage in rat brain 14 and 28 days after exposure to microwaves from GSM mobile phones.

We investigated the effects of global system for mobile communication (GSM) microwave exposure on the permeability of the blood-brain barrier and signs of neuronal damage in rats using a real GSM programmable mobile phone in the 900 MHz band. Ninety-six non-anaesthetized rats were either exposed to microwaves or sham exposed in TEM-cells for 2 h at specific absorption rates of average whole-body Specific Absorption Rates (SAR) of 0.12, 1.2, 12, or 120 mW/kg. The rats were sacrificed after a recovery time of either 14 or 28 d, following exposure and the extravazation of albumin, its uptake into neurons, and occurrence of damaged neurons was assessed. Albumin extravazation and also its uptake into neurons was seen to be enhanced after 14 d (Kruskal Wallis test: p = 0.02 and 0.002, respectively), but not after a 28 d recovery period. The occurrence of dark neurons in the rat brains, on the other hand, was enhanced later, after 28 d (p = 0.02). Furthermore, in the 28-d brain samples, neuronal albumin uptake was significantly correlated to occurrence of damaged neurons (Spearman r = 0.41; p < 0.01).

Radiofrequency and extremely low-frequency electromagnetic field effects on the blood-brain barrier.

During the last century, mankind has introduced electricity and during the very last decades, the microwaves of the modern communication society have spread a totally new entity--the radiofrequency fields--around the world. How does this affect biology on Earth? The mammalian brain is protected by the blood-brain barrier, which prevents harmful substances from reaching the brain tissue. There is evidence that exposure to electromagnetic fields at non thermal levels disrupts this barrier. In this review, the scientific findings in this field are presented. The result is a complex picture, where some studies show effects on the blood-brain barrier, whereas others do not. Possible mechanisms for the interactions between electromagnetic fields and the living organisms are discussed. Demonstrated effects on the blood-brain barrier, as well as a series of other effects upon biology, have caused societal anxiety. Continued research is needed to come to an understanding of how these possible effects can be neutralized, or at least reduced. Furthermore, it should be kept in mind that proven effects on biology also should have positive potentials, e.g., for medical use.

Anti-C1-inactivator treatment of glioblastoma.

PURPOSE: Glioblastoma multiforme (GBM) or astrocytoma grade IV is the most common type of primary brain tumor in adults. In the present study, we investigate the role of the complement system in the glioblastoma situation in an experimental model, since we have previously been able to show a blockade of this system in the glioblastoma setting. TECHNIQUE AND RESULTS: A GFP-positive glioblastoma cell line was used to induce glioblastomas subcutaneously in rats (n=42). Antibodies against C1-Inactivator (C1-IA) were used to try to re-activate the complement system. We were able to demonstrate an increased survival in rats treated with anti-C1-IA with an intratumoral route, and we could establish the same the results in a second series. Serum analyses revealed decreased levels of IL-1b and GM-CSF in animals 24 days after tumor cell inoculation in the anti-C1-IA group when compared to controls. Immunohistochemistry revealed decreased expression of C1-IA following treatment. INTERPRETATION: These results are in line with our previous work showing an upregulation of C1-IA, which is able to block the classical complement pathway, in glioblastomas. Treatment with antibodies against C1-IA seems to be beneficial in the glioblastoma situation, and no side effects could be seen in our experiments.

Evaluating vacquinol-1 in rats carrying glioblastoma models RG2 and NS1.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, and available experimental and routine therapies result in limited survival benefits. A vulnerability of GBM cells to catastrophic vacuolization and cell death, a process termed methuosis, induced by Vacquinol-1 (VQ-1) has been described earlier. In the present study, we investigate the efficacy of VQ-1 treatment in two syngeneic rat GBM models, RG2 and NS1. VQ-1 treatment affected growth of both RG2 and NS1 cells in vitro. Intracranially, significant reduction in RG2 tumor size was observed, although no effect was seen on overall survival. No survival advantage or effect on tumor size was seen in animals carrying the NS1 models compared to untreated controls. Furthermore, immunological staining of FOXP3, CD4 and CD8 showed no marked difference in immune cell infiltrate in tumor environment following treatment. Taken together, a survival advantage of VQ-1 treatment alone could not be demonstrated here, even though some effect upon tumor size was seen. Staining for immune cell markers did not indicate that VQ-1 either reduced or increased host anti-tumor immune response.

Low dose Zebularine treatment enhances immunogenicity of tumor cells.

STRATEGY: We have investigated how alterations in gene expression induced by the demethylating drug Zebularine affect the immune response tumor cells elicit. The rational has been to treat syngeneic rat colon cancer cells with Zebularine at different concentrations and then use these cells to study gene expression of different genes involved in cancer immunogenicity. Gene expressions were monitored by semi-quantitative PCR and real-time PCR. RESULTS: Intriguingly there was a large increase in the production of indoleamine 2,3-dioxygenase (IDO) after treatment with 100 microM Zebularine as compared with untreated tumor cells, whereas treatment with 20 microM Zebularine caused a significant decrease of the IDO production. After immunization with syngeneic tumor cells, spleen cells were isolated and restimulated in vitro with irradiated tumor cells. Immune reactivity was measured by proliferation, and production of interferon gamma and interleukin10. The immunogenicity of tumor cells treated in vitro with a low dose of Zebularine increased, whereas it decreased after high dose exposure. The inhibition of immunogenicity by 100 microM Zebularine was shown to be counteracted by the IDO inhibitor 1-methyl-tryptophan (1 MT), confirming that this effect of Zebularine is mainly caused by IDO induction. Differences using Zebularine-treated or non-treated cells for in vitro restimulation were marginal. CONCLUSION: Low dose treatment with Zebularine (20 microM) decreases the production of the immunosuppressive IDO from rat colon cancer cells and enhances their immunogenicity, whereas high dose Zebularine treatment (100 microM) enhances the IDO production from the cancer cells and suppresses their immunogenicity. This immunosuppression should be considered when cancer is treated with Zebularine or drugs acting in a similar way.

Lentiviral vector mediated siRNA knock-down of hTERT results in diminished capacity in invasiveness and in vivo growth of human glioma cells in a telomere length-independent manner.

Glioma cells are characterized by their invasiveness and resistance against conventional therapeutics. Telomerase activity has been suggested to be an important target for glioma treatment. Here we assessed the anticancer effects and its potential mechanisms of lentiviral vector mediated siRNA knock-down of the human telomerase reverse transcriptase (hTERT) in U87MG human glioblastoma cells. Stable expression of anti-hTERT siRNA reduced the hTERT expression and TRAP assay telomerase activity to barely detectable levels. Injection of lentiviral vectors encoding anti-hTERT siRNA significantly inhibited the growth of pre-established macroscopic xenograft tumors, which was in contrast to the finding that no obvious effects on cell growth, cell cycle progression and telomere length were observed in anti-hTERT siRNA expressing U87MG cells during short-term in vitro cultures. The in vivo glioma growth inhibition effect was already evident in the period coincided with no detectable telomere length changes, suggesting that hTERT inhibition may hinder glioma cell growth in a telomere length-independent manner. Importantly, transwell migration assay showed profound inhibitory effect on the invasive capacity of U87MG cells following short-term anti-hTERT siRNA expression. Thus, efficient knock-down of hTERT can inhibit glioma cell proliferation and migration prior to its effect on telomere length.

C1-inactivator is upregulated in glioblastoma.

BACKGROUND: Glioblastoma is the most common and aggressive type of primary brain tumor in adults. A key problem is the capacity of glioma cells to inactivate the body's immune response. The complement system acts as a functional bridge between the innate and adaptive immune response. Still, the role of the complement system has almost been forgotten in glioma research. In our present study, we hypothesize that C1 inactivator (C1-IA) is upregulated in astrocytoma grade IV, and that its inhibition of the complement system has beneficial effects upon survival. METHODS AND RESULTS: We have explored this hypothesis both on gene and protein levels and found an upregulation of C1-IA in human glioblastoma cells using data from a publicly available database and our own mRNA material from glioblastoma patients. Furthermore, we demonstrated the presence of C1-IA by using immunohistochemistry on glioma cells from both humans and rats in vitro. Finally, we could demonstrate a significantly increased survival in vivo in animals inoculated intracerebrally with glioma cells pre-coated with C1-IA antibodies as compared to control animals. CONCLUSIONS: Our findings indicate that overexpression of C1-IA is present in glioblastomas. This could be demonstrated both at the gene level from patients with glioblastoma, on mRNA level and with immunohistochemistry. Treatment with antibodies against C1-IA had beneficial effects on survival when tested in vivo.

Coxsackievirus and adenovirus receptor expression in non-malignant lung tissues and clinical lung cancers.

Adenoviral vector mediated gene delivery has been applied in clinical trials and mechanistic studies to explore new treatment approaches for lung cancers. The expression of coxsackievirus adenovirus receptor (CAR), the primary receptor for the most commonly used adenovirus serotype 5 (Ad5)-based vectors, predominantly determines the permissiveness of lung cancer cells. CAR expression is also suggested to modulate tumor cell proliferation capacity. Here, we studied CAR expression in archival lung cancer specimens by using well-characterized CAR 72 antibodies. High levels of CAR expression were observed in most of the 32 cases of squamous cell carcinoma lung cancers and in all the five cases of small cell lung cancers investigated. In contrast, high levels of CAR expression were detected only in 6 of 22 adenocarcinoma lung cancers. The relative levels of CAR expression did not correlate with the pathologic grade in lung cancers, and was thus inconsistent with a role of modulating cancer cell proliferation. Of note, CAR expression was not detected in non-malignant alveolar cells. Our data suggest a preferred utility of Ad5 vector mediated gene delivery to squamous cell carcinoma lung cancers, small cell lung cancers, but not to the majority of adenocarcinoma lung cancers.

99mTc-DTPA uptake and electrical impedance measurements in verification of in vivo electropermeabilization efficiency in rat muscle.

OBJECTIVE: In vivo electropermeabilization of cell membranes in rat muscle tissue cause a significant decrease of the electrical impedance, in the frequency region of 1-10 kHz. We aimed to study how the 99mTc-DTPA uptake in the electropermeabilized region correlates to the change of admittance Y = 1/absZ, where Z is the measured impedance. METHODS: The electropermeabilization was performed in vivo by applying high-voltage (0.5-2 kV) short (0.1-2 ms) pulses through gold-plated needle electrodes in skeletal muscle. The impedance was measured before and after each electropermeabilization pulse. The uptake of 99mTc-DTPA uptake in the electropermeabilized region was measured after 6 and 24 hours with a gamma camera. RESULTS: The pulse shape (square and exponential), duration, and amplitude of the applied electric field were varied, and electropermeabilization efficiency was evaluated using the various measurement modalities. Good correlations were found (correlation coefficient approximately 0.9) between the 99mTc-DTPA uptake in the electropermeabilized and control "region of interest" the admittance ratio Y (post-treatment)/Y (pretreatment), and charge displacement parameter Q. CONCLUSION: The electrical impedance measurements method can be utilized in clinical settings to verify the efficiency of electropermeabilization applied to chemotherapy and to power RNAi (RNA-interference) and DNA-plasmid transfection in vaccination, immunization, and gene-therapy.

ITPP Treatment of RG2 Glioblastoma in a Rat Model.

BACKGROUND: Inositol trispyrophosphate (ITPP) has been shown to reduce tumour growth in different animal cancer models, as well as of human U87 glioma cells grafted onto chick chorioallantoic membrane (CAM). The aim of this study was to establish whether ITPP crosses the blood-brain barrier and whether it halts the growth of RG2 glioblastoma tumour. MATERIALS AND METHODS: A model comprising of Fischer 344 rats was chosen and RG2 cells were implanted either intracranially, or subcutaneously on the left hind leg, and the animals were treated with ITPP either intraperitoneally, intravenously or both routes combined. Overall survival was then calculated. RESULTS: No prolonged survival was seen in animals treated with ITPP. The route of ITPP administration did not affect outcome. CONCLUSION: ITPP had no favourable effect upon survival in our animal model with RG2 glioblastoma tumours in Fischer 344 rats.