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At least 721 records · Page 40Linked to original sources
PubMed2002

Combined radiation and gene therapy for brain tumors with adenovirus-mediated transfer of cytosine deaminase and uracil phosphoribosyltransferase genes.

Radiation therapy is an established modality for the treatment of malignant gliomas. Several reports have shown the advantage of additional radiation in combination with gene therapy. In this study, we investigated the ability of radiation therapy to enhance 5-fluorocytosine (5-FC)/cytosine deaminase (CD) plus uracil phosphoribosyltransferase (UPRT) gene therapy in malignant gliomas. In vitro study suggested evidence of a significant cytotoxic interaction between radiation therapy and 5-FC/CD + UPRT gene therapy for glioma cells. In vivo experiments demonstrated that the combination of gene therapy and radiation possessed superior antitumor effect in comparison to single therapy. However, the adverse effects of radiation therapy in combination with the gene therapy were observed with respect to normal brain. This combination therapy may be feasible for the treatment of gliomas, although the radiation dose and area should be reduced in order to prevent side effects.

Adenoviridae↗
PubMedDate not supplied

Magnetic labeling of activated microglia in experimental gliomas.

Microglia, as intrinsic immunoeffector cells of the central nervous system (CNS), play a very sensitive, crucial role in the response to almost any brain pathology where they are activated to a phagocytic state. Based on the characteristic features of activated microglia, we investigated whether these cells can be visualized with magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxides (USPIOs). The hypothesis of this study was that MR microglia visualization could not only reveal the extent of the tumor, but also allow for assessing the status of immunologic defense. Using USPIOs in cell culture experiments and in a rat glioma model, we showed that microglia can be labeled magnetically. Labeled microglia are detected by confocal microscopy within and around tumors in a typical border-like pattern. Quantitative in vitro studies revealed that microglia internalize amounts of USPIOs that are significantly higher than those incorporated by tumor cells and astrocytes. Labeled microglia can be detected and quantified with MRI in cell phantoms, and the extent of the tumor can be seen in glioma-bearing rats in vivo. We conclude that magnetic labeling of microglia provides a potential tool for MRI of gliomas, which reflects tumor morphology precisely. Furthermore, the results suggest that MRI may yield functional data on the immunologic reaction of the CNS.

Animals↗
PubMedDate not supplied

Combination of endostatin and a protein kinase Calpha DNA enzyme improves the survival of rats with malignant glioma.

Malignant gliomas are refractory to conventional therapies, including surgery, radiotherapy and chemotherapy. Thus, a variety of therapies such as the inhibition of angiogenesis and signal transduction pathways have been attempted. In the present study, we have evaluated the combined effect of endostatin, an inhibitor of angiogenesis, and a DNA enzyme targeting the protein kinase Calpha (PKCalpha) gene expression. Inhibition of PKCalpha by a nuclease-resistant DNA enzyme eliminated PKCalpha gene expression and induced apoptosis in most glioma cells. To assess the efficacy of endostatin and the PKCalpha DNA enzyme in vivo, rats bearing the intracranial tumor BT(4)C were given a combined treatment of endostatin and the PKCalpha enzyme. Survival was significantly enhanced by continuous delivery of endostatin (P<.0004) and rats treated with a single injection of the active DNA enzyme lived significantly longer than those treated with the inactive form (P<.045). Interestingly, a single injection of the PKCalpha DNA enzyme in combination with continuous delivery of endostatin significantly improved animal survival compared with PKCalpha (P<.0009) or endostatin (P<.025) alone. Thus, the combined treatment may represent an attractive therapeutic strategy against malignant gliomas.

Angiogenesis Inhibitors↗
PubMed2000

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Adult↗
PubMed2004

Image-guided robotic radiosurgery in a rat glioma model.

Despite the proven efficacy of radiosurgery for the treatment of brain tumors, limited histological information is available after treatment that might allow a better understanding of the relationship between radiation dose, the volume treated, and the response of the surrounding brain to the delivered radiation. The use of an animal model could provide the opportunity to clarify these relationships and answer several other key questions arising in clinical practice. We show here that treatment of small animals with radiosurgery is feasible using a robotically controlled linear accelerator, which offers the advantages of radiosurgery and preserves the potential for fractionated regimens without rigid immobilization. Specifically, we demonstrate the use of a robotically driven linear accelerator to provide radiosurgical treatment to a rat brain tumor model.

Animals↗
PubMed1995

Localization of superficial cerebral lesions using a magnetic resonance imaging-guided localizer.

The localization of superficial cerebral lesions may be difficult even if they reach the surface of the cerebral cortex. Intraoperative ultrasound often fails to detect subcortical lesions. A localization device using multiplanar MR-imaging has been designed to project such lesions to the scalp. This device is a hood-shaped grid made of polyethylene tubing filled with paramagnetic contrast agent. In this hemispherical grid the tubes are arranged at a distance of 15 to 30 mm so that the MR-plane always slices perpendicular to the axis of the tubing and depicts a bright spot per tube. It is rapidly filled prior to each MR-examination, placed on the patient's head, and taped to his forehead to avoid unintentional displacement during and after the examination until the projection of the lesion is marked on the skin.

Brain Neoplasms↗
PubMed2003

A novel neurotropic expression vector based on the avirulent A7(74) strain of Semliki Forest virus.

Semliki Forest virus (SFV), an enveloped alphavirus of the family Togaviridae, infects a wide range of mammalian host cells. Most strains are neurotropic but differ in virulence. The authors took advantage of the nonpathogenic properties of SFV strain A7(74), cloned recently in their laboratory, and constructed a replication-proficient expression vector to target the central nervous system (CNS) for heterologous gene expression. The vector, termed VA7, was engineered to drive expression of foreign inserts through a second subgenomic promoter inserted in the viral 3' nontranslated region (NTR). Infectious virus was obtained by in vitro transcription and transfection into BHK cells, and was shown to direct synthesis of heterologous proteins in several mammalian cell lines. Although novel expression vehicle is not applicable for targeting specific cell populations within the CNS in its present form, in cultured rat hippocampal slices, VA7 encoding enhanced green fluorescent protein (EGFP) efficiently transduced pyramidal cells, interneurons, and glial cells. With prolonged time post infection, the number of EGFP-expressing neurons in hippocampal slices increased. Mice infected intraperitoneally with the recombinant virus remained completely asymptomatic but showed CNS expression of EGFP as evidenced by immunohistochemistry. SFV A7(74) is a nonintegrating virus, which gives rise to a randomly distributed, patchy infection of the adult CNS that is cleared within 10 days. With the advantage of noninvasive administration, the expression vector described in this work is thus applicable for short-term gene expression in the CNS.

Animals↗
PubMed1998

Induction of cytotoxic oxidative stress by D-alanine in brain tumor cells expressing Rhodotorula gracilis D-amino acid oxidase: a cancer gene therapy strategy.

Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) generated in the stereoselective deamination of D-amino acids catalyzed by D-amino acid oxidase (DAAO). H2O2 readily crosses cellular membranes and damages DNA, proteins, and lipids. The scarcity of DAAO substrates in mammalian organisms and its co-localization with catalase in the peroxisomal matrix suggested that the cytotoxicity of ROS could be harnessed by administration of D-amino acids to tumor cells ectopically expressing DAAO in the cytoplasm. To evaluate this hypothesis, the cDNA encoding the highly active DAAO from the red yeast Rhodotorula gracilis was mutated to remove the carboxy-terminal peroxisomal targeting sequence. A clonal line of 9L glioma cells stably transfected with this construct (9Ldaao17) was found to synthesize active R. gracilis DAAO. Exposure of 9Ldaao17 cells to D-alanine resulted in cytotoxicity at concentrations that were nontoxic to parental 9L cells. Depletion of cellular glutathione further sensitized 9Ldaao17 cells to D-alanine (D-Ala). This result, combined with stimulation of pentose phosphate pathway activity and the production of extracellular H2O2 by 9Ldaao17 cells incubated with D-alanine implicates oxidative stress as the mediator of cytotoxicity. These results demonstrate that expression of R. gracilis DAAO in tumor cells confers chemosensitivity to D-alanine that could be exploited as a novel cancer gene therapy paradigm.

Alanine↗
PubMed1998

New prodrug activation gene therapy for cancer using cytochrome P450 4B1 and 2-aminoanthracene/4-ipomeanol.

Vector-mediated transfer of prodrug-activating genes provides a promising means of cancer gene therapy. In a search for more selective and more potent bioactivating enzymes for gene therapy of malignant brain tumors, the toxicity-generating capacity of the rabbit cytochrome P450 isozyme CYP4B1 was investigated. Rabbit CYP4B1, but not rat or human isozymes, efficiently converts the inert prodrugs, 2-aminoanthracene (2-AA) and 4-ipomeanol (4-IM), into highly toxic alkylating metabolites. Toxicity of these two prodrugs was evaluated in culture in parental and genetically modified rodent (9L) and human (U87) glioma cell lines stably expressing CYP4B1, and in vivo in a subcutaneous 9L tumor model in nude mice. The most sensitive CYP4B1-expressing glioma clone, 9L4B1-60, displayed an LD50 of 2.5 microM for 2-AA and 4-IM after 48 h of prodrug incubation, whereas 20 times higher prodrug concentrations did not cause any significant toxicity to control cells. Substantial killing of control tumor cells by 2-AA was achieved by co-culturing these cells with CYP4B1-expressing cells at a ratio of 100:1, and toxic metabolites could be transferred through medium. In both CYP4B1-expressing cells and co-cultured control cells, prodrug bioactivation was associated with DNA fragmentation, as assayed by fluorescent TUNEL assays and by annexin V staining. Alkaline elution of cellular DNA after exposure to 4-IM revealed extensive protein-DNA crosslinking with single-strand breakage. Growth of 9L-4B1 tumors in nude mice was inhibited by intraperitoneal injection of 4-IM with minimal side effects. Potential advantages of the CYP4B1 gene therapy paradigm include: the low concentrations of prodrug needed to kill sensitized tumor cells; low prodrug conversion by human isozymes, thus reducing toxicity to normal cells; a tumor-killing bystander effect that can occur even without cell-to-cell contact; and the utilization of lipophilic prodrugs that can penetrate the blood-brain barrier.

Animals↗
PubMed1997

Evaluation of lipid-coated microbubbles as a delivery vehicle for Taxol in brain tumor therapy.

OBJECTIVE: This work evaluates the potential of lipid-coated microbubbles (LCM) as a delivery vehicle for lipid-soluble antineoplastic agents. We have shown, in rats, the selective affinity of intravenously administered LCM for tumor cells. They are internalized by the tumor cells both in vitro and in vivo. The specificity of LCM for tumors and subsequent incorporation into the cytoplasm could significantly reduce the systemic effects of an agent incorporated into the bubbles, such as Taxol. METHODS: The in vitro methods were as follows. C6 cells (10(5) cells) were treated with Taxol-LCM (6 micrograms/ml), Taxol-Cremophore (6 micrograms/ml), or LCM alone for 8 or 24 hours. Cell death was determined by staining the cells with nuclear staining. Abnormalities of microtubule structures were ascertained by confocal microscopy. The in vivo methods were as follows. Two rat tumor models (C6 and 9L) were used. Rats were treated with single bolus injections or with repetitive (two or three) treatment courses, with respective control animals. Each course consisted of one daily tail vein injection for 5 consecutive days and then 2 days of rest. RESULTS: When compared with either a saline control group or a group receiving Taxol in an oil vehicle, Taxol-LCM reduced tumor progression in Fischer 344 rats inoculated with 9L glioma. The most profound effect was observed with rats treated with three treatment cycles (five daily injections/cycle) separated by two rest periods (2 d/period). CONCLUSION: Both in vitro and in vivo data indicate that Taxol can be incorporated into LCM, can be delivered to the tumor site, and can exert a measurable antitumor biological effect.

Animals↗
PubMed2002

7-Hydroxystaurosporine-induced apoptosis in 9L glioma cells provides an effective antigen source for dendritic cells and yields a potent vaccine strategy in an intracranial glioma model.

OBJECTIVE: On the basis of recent studies indicating that tumoral apoptotic bodies may provide a potent source of antigen for delivery to antigen-presenting cells, as well as observations that signal transduction modulation may constitute a promising approach for inducing glioma cell apoptosis, we explored the efficacy of vaccination with glioma apoptotic body-pulsed dendritic cells (DCs) for inhibiting tumor growth in the syngeneic 9L glioma/Fischer rat model. METHODS: For induction of apoptosis, 7-hydroxystaurosporine (UCN-01) (200-300 ng/ml), a selective protein kinase C inhibitor, was co-incubated with 9L cells in vitro for 72 or 96 hours. After this pretreatment period, glioma cells and DCs were mixed, and the interaction between DCs and apoptotic 9L tumor cells was assessed using two-color flow cytometry. In a series of experiments, the efficacy of vaccination strategies using DCs co-cultured with apoptotic 9L cells was then examined in animals harboring intracranial tumors. RESULTS: Pretreatment of 9L cells with UCN-01 resulted in approximately 50% of cells' being observed to undergo apoptosis as compared with less than 3% of controls. After subsequent co-culture, two-color flow cytometry demonstrated a time-dependent physical association of DCs with the apoptotic glioma cells. Survival in animals harboring intracranial tumors was significantly longer for the animals treated with a glioma apoptotic body-pulsed DC vaccine than in the animals that received apoptotic glioma cells and DCs alone or vehicle (i.e., the controls), especially those that underwent a sequential vaccination strategy (P < 0.0001). Long-term survival (>90 d) was demonstrated in 6 (75%) of 8 animals that underwent this vaccination approach versus 0 (0%) of 16 controls. In contrast, no survival benefit was observed in animals that received DCs that were co-cultured with vehicle-treated (non-apoptotic) 9L cells. Three of four long-term survivors that were rechallenged intracranially with tumor cells also survived over the long term. CONCLUSION: These studies suggest that induction of apoptosis in glioma cells by use of UCN-01 may promote the uptake of tumor antigens by DCs. This finding is important because apoptotic body-stimulated DCs may hold promise in promoting a host response against an established intracranial glioma, particularly if the parameters for apoptotic induction, duration of co-culture, and vaccination can be optimized.

Alkaloids↗
PubMed2004

Analysis of boron-10 in soft tissue by dynamic secondary ion mass spectrometry.

We report here a preliminary study in which dynamic secondary ion mass spectrometry (SIMS) has provided images of boron-10 (10B) in biological tissue as used in research into boron neutron capture therapy. Cultured tumour cells incubated in media containing known concentrations of a 10B-containing compound, p-boronophenylalanine (BPA), and intracranial tumour tissue from animals previously injected with BPA were analysed by an in-house constructed SIMS. Investigations were conducted in positive secondary ion detection mode using a 25-keV, 5-nA gallium primary ion source. For calibration purposes, tissue standards were also analysed and their boron-to-carbon signal ratios correlated to bulk boron concentrations measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Ion maps of 10B, 12C, 23Na and 39K showing gross tissue and cell features were acquired. SIMS and ICP-AES standard measurements were in good agreement. Tissue regions with high or low 10B concentrations were identified along with 10B hotspots in normal brain areas. Cultured cells revealed the intracellular localization of 10B. SIMS is capable of producing images showing the distribution of 10B at p.p.m. levels in cells and in normal and tumour-bearing brain tissue.

Animals↗
PubMed2004

Antitumor activity of methoxymorpholinyl doxorubicin: potentiation by cytochrome P450 3A metabolism.

Methoxymorpholinyl doxorubicin (MMDX) is a novel liver cytochrome P450 (P450)-activated anticancer prodrug whose toxicity toward cultured tumor cells can be potentiated up to 100-fold by incubation with liver microsomes and NADPH. In the present study, a panel of human liver microsomes activated MMDX with potentiation ratios directly correlated to the CYP3A-dependent testosterone 6beta-hydroxylase activity of each liver sample. Microsome-activated MMDX exhibited nanomolar IC(50) values in growth-inhibition assays of human tumor cell lines representing multiple tissues of origin: lung (A549 cells), brain (U251 cells), colon (LS180 cells), and breast (MCF-7 cells). Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4 activated MMDX more efficiently than rat CYP3A2 and that human P450s 3A5 and 3A7 displayed little or no activity. MMDX cytotoxicity was substantially increased in Chinese hamster ovary cells after stable expression of CYP3A4 in combination with P450 reductase. CYP3A activation of MMDX abolished the parent drug's residual cross-resistance in a doxorubicin-resistant MCF-7 cell line that overexpresses P-glycoprotein. CYP3A-activated MMDX displayed a comparatively high intrinsic stability, with a t(1/2) of approximately 5.5 h at 37 degrees C. MMDX was rapidly activated by CYP3A at low ( approximately 1-5 nM) prodrug concentrations, with 100% tumor cell kill obtained after as short as a 2-h exposure to the activated metabolite. These findings demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-permeable cytotoxic metabolite and suggest that this anthracycline prodrug may be used in combination with CYP3A4 in a P450 prodrug activation-based gene therapy for cancer treatment.

Animals↗
PubMed1999

B-myb promoter retargeting of herpes simplex virus gamma34.5 gene-mediated virulence toward tumor and cycling cells.

Deletion of the gamma34.5 gene coding for virulence markedly reduces cytotoxicity mediated by herpes simplex virus type 1 (HSV-1) (J. M. Markert et al., Neurosurgery 32:597-603, 1993; N. S. Markovitz et al. , J. Virol. 71:5560-5569, 1997). To target lytic virulence to tumors, we have created a novel HSV-1 mutant, designated Myb34.5. This viral mutant is characterized by a deletion of the gene for infected cell polypeptide 6 (ICP6; also known as UL39 or ribonucleotide reductase) and of the two endogenous copies of the gamma34.5 gene (RL1) and by reintroduction of one copy of gamma34.5 under control of the E2F-responsive, cellular B-myb promoter. On direct intracerebral inoculation in BALB/c mice, the 50% lethal dose (LD(50)) for Myb34.5 was 2.7 x 10(7) PFU while that for HSVs with mutations in the gamma34.5 gene could not be technically achieved with available viral stocks and it was estimated as >1 x 10(7) PFU. The LD(50) for an HSV with a single defect in ICP6 function was 1.3 x 10(6) PFU. Conversely, Myb34.5's oncolytic efficacy against a variety of human glioma cells in culture and in vivo was enhanced compared to that of HSVs with gamma34.5 mutations, and in fact, it was comparable to that of the wild-type F strain and of viral mutants that possess a wild-type gamma34.5 gene. The characteristic shutoff of host protein synthesis, occurring after infection of human SK-N-SH neuroblastoma cells by gamma34.5 mutant viruses (J. Chou and B. Roizman, Proc. Natl. Acad. Sci. USA 89:3266-3270, 1992), was not present after infection with Myb34.5. There was an increase of almost 3 logarithmic units in the production of progeny virus in arrested fibroblasts compared to that in cycling fibroblasts infected with Myb34.5. These results suggest that transcriptional regulation of gamma34.5 by cell cycle-regulated promoters can be used to target HSV-1 virulence toward tumors while maintaining the desirable neuroattenuated phenotype of a gamma34.5 mutant.

Animals↗