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PubMed2004

Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging.

Although liposomes have been used as a vehicle for delivery of therapeutic agents in oncology, their efficacy in targeting brain tumors has been limited due to poor penetration through the blood-brain barrier. Because convection-enhanced delivery (CED) of liposomes may improve the therapeutic index for targeting brain tumors, we conducted a three-stage study: stage 1 established the feasibility of using in vivo magnetic resonance imaging (MRI) to confirm adequate liposomal distribution within targeted regions in normal rat brain. Liposomes colabeled with gadolinium (Gd) and a fluorescent indicator, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-5,5'-disulfonic acid [DiI-DS; formally DiIC(18)(3)-DS], were administered by CED into striatal regions. The minimum concentration of Gd needed for monitoring, correlation of infused volume with distribution volume, clearance of infused liposome containing Gd and DiI-DS (Lip/Gd/DiI-DS), and potential local toxicity were evaluated. After determination of adequate conditions for MRI detection in normal brain, stage 2 evaluated the feasibility of in vivo MRI monitoring of liposomal distribution in C6 and 9L-2 rat glioma models. In both models, the distribution of Lip/Gd/DiI-DS covering the tumor mass was well defined and monitored with MRI. Stage 3 was designed to develop a clinically relevant treatment strategy in the 9L-2 model by infusing liposome containing Gd (Lip/Gd), prepared in the same size as Lip/Gd/DiI-DS, with Doxil, a liposomal drug of similar size used to treat several cancers. MRI detection of Lip/Gd coadministered with Doxil provided optimum CED parameters for complete coverage of 9L-2 tumors. By permitting in vivo monitoring of therapeutic distribution in brain tumors, this technique optimizes local drug delivery and may provide a basis for clinical applications in the treatment of malignant glioma.

Animals↗
PubMed2005

Tomographic fluorescence mapping of tumor targets.

Methods that allow robust imaging of specific molecular targets and biological processes in vivo should have widespread applications in biology and clinical medicine. Here we use a quantitative, three-dimensional fluorescence-mediated tomographic technique (FMT) that enables rapid measurements of fluorochrome-based affinity tags in live xenograft models. We validate the method by showing its sensitivity in quantitating tumor angiogenesis and therapeutic modulation using an anti-vascular endothelial growth factor antibody. Furthermore, we show the feasibility of simultaneous multichannel measurements of distinct biological phenomena such as receptor tyrosine kinase expression and angiogenesis. FMT measurements can be done serially, with short imaging times and within the same live animal. The described method should be valuable for rapidly profiling biological phenomena in vivo.

Animals↗
PubMed2005

Recombinant Sendai virus vector induces complete remission of established brain tumors through efficient interleukin-2 gene transfer in vaccinated rats.

PURPOSE: Sendai virus (SeV), a murine parainfluenza virus type I, replicates independent of cellular genome and directs high-level gene expressions when used as a viral vector. We constructed a nontransmissible recombinant SeV vector by deleting the matrix (M) and fusion (F) genes from its genome (SeV/DeltaMDeltaF) to enhance its safety. We also estimated the therapeutic efficacy of the novel vector system against a rat glioblastoma model. EXPERIMENTAL DESIGN: We administered the recombinant SeV vector carrying the lacZ gene or the human interleukin-2 (hIL-2) gene into established 9L brain tumors in vivo simultaneous with peripheral vaccination using irradiated 9L cells. Sequential monitoring with magnetic resonance imaging was used to evaluate the therapeutic efficacy. RESULTS: We found extensive transduction of the lacZ gene into the brain tumors and confirmed sufficient amounts of interleukin 2 (IL-2) production by hIL2-SeV/DeltaMDeltaF both in vitro and in vivo. The magnetic resonance imaging study showed that the intracerebral injection of hIL2-SeV/DeltaMDeltaF brought about significant reduction of the tumor growth, including complete elimination of the established brain tumors. The (51)Cr release assay showed that significant amounts of 9L-specific cytotoxic T cells were induced by the peripheral vaccination. Immunohistochemical analysis revealed that CD4(+) T cells and CD8(+) T cells were abundantly infiltrated in the target tumors. CONCLUSION: The present results show that the recombinant nontransmissible SeV vector provides efficient in vivo gene transfer that induces significant regression of the established brain tumors and suggest that it will be a safe and useful viral vector for the clinical practice of glioma gene therapy.

Animals↗
PubMed2005

Effect of repetitive administration of Doxorubicin-containing liposomes on plasma pharmacokinetics and drug biodistribution in a rat brain tumor model.

PURPOSE: The incorporation of doxorubicin in long-circulating sterically stabilized liposomes (SSL-DXR) alters the pharmacokinetics and biodistribution of doxorubicin and therefore has the potential to alter the pharmacologic properties of doxorubicin. Previously, we showed that repetitive administration of SSL-DXR alters tumor vascular permeability. EXPERIMENTAL DESIGN: Here, we investigated the effect of weekly i.v. injections of SSL-DXR on plasma pharmacokinetics and drug biodistribution in the orthotopic 9L rat brain tumor model. RESULTS AND CONCLUSIONS: The pharmacokinetics of free doxorubicin (5.67 mg/kg) did not change with repeat dosing. In contrast, drug concentrations in plasma and brain tumor increased and deposition in liver and spleen decreased after administration of the second of two weekly doses of SSL-DXR. Noncompartmental analysis and descriptive pharmacokinetic models were created to test hypotheses relating to the mechanisms responsible for alterations in SSL-DXR deposition. The analysis suggested that weekly administration of SSL-DXR significantly (P < 0.05) decreased the plasma elimination rate of SSL-DXR (34%) and decreased drug deposition in liver (2-fold) and spleen (3.5-fold). The pharmacokinetic model that best captured the observed 2.5-fold increase in tumor uptake of SSL-DXR mediated by repeat dosing was one that hypothesized that the rates of drug influx/efflux into tumor were increased by the first dose of SSL-DXR. Models that accounted only for residual drug deposited in the tissue or blood by the first weekly injection provided inferior fits to the data. Thus, the effects of repetitive dosing on SSL-DXR deposition in tumor are consistent with a treatment-mediated alteration of tumor vascular permeability.

Animals↗
PubMed1997

lacZ transduction of 9L rat tumor cells without cloning.

Several laboratories have introduced the lacZ gene into 9L cells to improve the usefulness of this already popular rat brain tumor model. However, these laboratories were not concerned about possible changes in the phenotypic characteristics of the 9L cell line which can be induced by the selection of lacZ-expressing clones. Here, we describe a method for introducing the lacZ gene into 9L cells without selective cloning. The 9L parent cells (passaged the same number of times) and 9L/lacZ cells were compared in a number of tests and found to have the same phenotype. Specifically, they had the same sensitivity to radiation from external gamma or internal beta radiation, the same growth rates with or without frequent media changes and the same patterns of growth in rat brain. We demonstrated that the 9L/lacZ cells could be sorted from dissociated tumors by flow cytometry and the percentage of nonmalignant versus malignant cells determined. These percentages were variable from rat to rat. The colony-forming efficiency could be determined on the basis of whole tumor or, by using the percent of lacZ-positive cells, on the basis of malignant cells in a tumor. These novel approaches should render the 9L tumor model even more useful.

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PubMed2006

Detrimental effects of tumor progression on cognitive function of patients with high-grade glioma.

PURPOSE: There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed. PATIENTS AND METHODS: We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time. RESULTS: The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression. CONCLUSION: The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.

Adult↗
PubMed2006

Nanoparticle imaging of integrins on tumor cells.

Nanoparticles 10 to 100 nm in size can deliver large payloads to molecular targets, but undergo slow diffusion and/or slow transport through delivery barriers. To examine the feasibility of nanoparticles targeting a marker expressed in tumor cells, we used the binding of cyclic arginine-glycine-aspartic acid (RGD) nanoparticle targeting integrins on BT-20 tumor as a model system. The goals of this study were: 1) to use nanoparticles to image alpha(V)beta3 integrins expressed in BT-20 tumor cells by fluorescence-based imaging and magnetic resonance imaging, and, 2) to identify factors associated with the ability of nanoparticles to target tumor cell integrins. Three factors were identified: 1) tumor cell integrin expression (the alpha(V)beta3 integrin was expressed in BT-20 cells, but not in 9L cells); 2) nanoparticle pharmacokinetics (the cyclic RGD peptide cross-linked iron oxide had a blood half-life of 180 minutes and was able to escape from the vasculature over its long circulation time); and 3) tumor vascularization (the tumor had a dense capillary bed, with distances of <100 microm between capillaries). These results suggest that nanoparticles could be targeted to the cell surface markers expressed in tumor cells, at least in the case wherein the nanoparticles and the tumor model have characteristics similar to those of the BT-20 tumor employed here.

Animals↗
PubMed1997

Effect of adenoviral-mediated thymidine kinase transduction and ganciclovir therapy on tumor-associated endothelial cells.

Transduction of the herpes simplex virus thymidine kinase (HSV-tk) into vascular endothelial cells using a replication-defective adenoviral vector (Ad.CMV-tk) to confer sensitivity to ganciclovir (GCV) was investigated. The cytotoxic sensitivity of bovine aortic endothelial cells (BAEC) to GCV following Ad.CMV-tk transduction at multiplicity of infection of 100 was ten-fold that of 9L glioma cells in vitro. Deoxyribonucleic acid fragmentation was detected in these BAEC. A co-culture experiment using BAEC transduced with Ad.CMV-tk (BAEC-tk) and 9L cells expressing beta-galactosidase (9L-Lac Z) showed about 70% tumoricidal effect under the conditions of one BAEC-tk cell in 10 9L-Lac Z cells. Tumor-bearing Fisher 344 rats, an experimental brain tumor model, received Ad.CMV-tk intratumorally at 7 days after tumor implantation, and were subsequently treated with intraperitoneal GCV (100 mg/kg). Histological examination found the vascular endothelial cells adjacent to 9L glioma tissue revealed apoptosis. These results suggest that vascular endothelial cells are an attractive target for adenoviral-mediated HSV-tk gene therapy.

Adenoviridae↗
PubMed2000

Time course analysis and modulating effects of established brain tumor on active-specific immunotherapy.

OBJECT: There have been numerous attempts to establish an effective immunotherapy for the treatment of brain tumors. To date, reliable methods to manipulate the immune system for promoting brain tumor regression have been disappointing. Generation of active immune responses in most of these studies was only possible in the absence of viable tumor cells, suggesting that immunotherapy can only be used as preventive therapy. In few studies the investigators have demonstrated success in using immunotherapy to treat a preestablished intracranial tumor. Using the 9L intracranial glioma model, the authors sought to delineate the underlying mechanisms for these observations. METHODS: In animals vaccinated with irradiated 9L glioma cells and interferon-gamma 14 and 7 days prior to intracranial tumor cell challenge, a significant increase in survival was shown. In contrast, vaccinations applied 3 days prior to, at the time of (Day 0) or 7 days after intracranial tumor cell challenge failed to influence survival. Histological examination of brain tissue specimens obtained in animals vaccinated before or after tumor cell challenge showed no difference in the degree of peritumoral mononuclear cell infiltration. When activated spleen cells obtained obtained from these animals were assayed for cytotoxicity and proliferative capacity, only those spleen cells derived from animals vaccinated prior to intracranial tumor cell challenge showed enhanced activity. CONCLUSIONS: These data support the presence of a strong modulatory effect of tumor on local and systemic antitumoral immune response. This immunosuppression appears to be secondary to a direct effect on T-cell function. Reversal of this immunosuppression may be a useful adjunct to tumor vaccine therapy.

Animals↗
PubMed1998

Increased uptake of 99mTc-HMPAO in necrotic brain tumors.

99mTc complex of hexamethylpropylene amine oxime (99mTc-HMPAO), which has been used as a tracer for regional cerebral blood flow (rCBF), has been shown to localize in primary brain tumors with wide spectrum of its uptake. The causes of the wide spectrum of tumor uptake, however, has not been understood in detail. We performed autoradiographic study with this agent to get further knowledge about HMPAO distribution in 10 cases of transplanted rat gliomas. Eight cases of rat gliomas without tumor necrosis, showed decreased uptake of 99mTc-HMPAO in the autoradiography (average tumor/normal (T/N) uptake ratio: 0.75, range: 0.40-0.90). On the other hand, two cases with tumor necrosis revealed increased uptakes of this agent in central necrotic area. T/N uptake ratios of these two cases were 1.23 and 1.42, respectively. In addition, three patients with histologically proven glioblastoma with tumor necrosis were studied after administration of 20mCi 99mTc-HMPAO. Two out of three patients showed higher uptake of 99mTc-HMPAO in tumor necrotic area than the contralateral area. Our findings suggest that the necrotic area of brain tumor may retain 99mTc-HMPAO and causes an increased uptake.

Animals↗
PubMed1999

Enhanced uptake of [11C]TPMP in canine brain tumor: a PET study.

UNLABELLED: In vitro studies have demonstrated the membrane potential-dependent enhanced uptake of phosphonium salts, including [3H]triphenylmethylphosphonium (TPMP), into mitochondria of carcinoma and glioma-derived tumor cells, suggesting the potential use of phosphonium salts as tracers for tumor imaging. This study characterizes the in vivo uptake of [11C]TPMP in canine brain glioma using PET. METHODS: Dynamic paired PET studies of [11C]TPMP followed by [68Ga]ethylenediaminetetraacetic acid (EDTA) were performed 4 d before and 9 d after tumor cell inoculation. Graphical analysis was used to evaluate [11C]TPMP retention in tumor tissue. Distribution of tracer uptake was compared with tumor histological sections. RESULTS: [11C]TPMP exhibited enhanced uptake and prolonged retention in tumor cells. Patlak plot was linear over the 20- to 95-min postinjection period (r = 0.97 +/- 0.1). [68Ga]EDTA exhibited a gradual washout from the tumor tissue. The tumor-to-normal brain uptake ratio at 55 to 95 min postinjection was 47.5 for [11C]TPMP and 8.1 for [68Ga]EDTA. Qualitative comparison with histological sections indicated that [11C]TPMP enhanced uptake was restricted to the tumor area. CONCLUSION: The enhanced uptake and prolonged retention in tumor suggest [11C]TPMP as a promising means for imaging of gliomas in dogs. The need for studies in humans is indicated.

Animals↗
PubMed2000

Vascular protection by chloroquine during brain tumor therapy with Tf-CRM107.

Tf-CRM107 is a conjugate of transferrin and a point mutant of diphtheria toxin that selectively kills cells expressing high levels of the transferrin receptor. Tf-CRM107 has been infused intratumorally into patients with malignant brain tumors. Although approximately half of the patients exhibit tumor responses, patients receiving higher doses of Tf-CRM107 may develop magnetic resonance image (MRI) evidence of toxicity indicative of small vessel thrombosis or petechial hemorrhage. Consistent with these clinical results we found that intracerebral injection of Tf-CRM107 into rats at total doses > or =0.025 microg causes brain damage detectable by MRI and histology. To widen the therapeutic window of Tf-CRM107, we explored ways to prevent this damage to the vasculature. We reasoned that the vasculature may be protected to a greater extent than tumor from Tf-CRM107 infused into brain parenchyma by i.v. injection of reagents with low blood-brain barrier permeability that block the toxicity of Tf-CRM107. Chloroquine, a well-characterized antimalarial drug, blocks the toxicity of diphtheria toxin and Tf-CRM107. Systemic administration of chloroquine blocked the toxicity of Tf-CRM107 infused intracerebrally in rats and changed the maximum tolerated dose of Tf-CRM107 from 0.2 to 0.3 microg. Moreover, chloroquine treatment completely blocked the brain damage detected by MRI caused by intracerebral infusion of 0.05 microg of Tf-CRM107. In nude mice bearing s.c. U251 gliomas, chloroquine treatment had little effect on the antitumor efficacy of Tf-CRM107. Thus, chloroquine treatment may be useful to reduce the toxicity of Tf-CRM107 for normal brain without inhibiting antitumor efficacy and increase the therapeutic window of Tf-CRM107 for brain tumor therapy.

Animals↗
PubMed2000

[Malignant glial tumor with skeletal muscle differentiation. Description of a case].

A case of CNS gliomyosarcoma, in a 71-year-old female with skeletal muscle differentiation is presented. The tumor was composed by two cell types: one showed features typical of glial cells, the other was constituted by elements having immunohistochemical positivity with desmin, sarcomeric actin, myoglobin and myogenin antisera. It is postulated an origin from a cell capable of dual differentiation.

Actins↗
PubMedDate not supplied

Measurement of sister chromatid exchange induction in intracerebral brain tumors as a method for evaluation of therapeutic drug combinations.

Rats with 9L or 9L-2 intracerebral brain tumors were treated with streptozotocin (STZ) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) at various doses either as single agents or in combination. Treatment of rats bearing 9L or 9L-2 tumors with either STZ or BCNU produced a significant increase the level of sister chromatid exchanges (SCEs) (p < .001). Compared with 9L-2 tumors, 9L tumors were 7.8-fold more sensitive to the induction of SCEs by BCNU treatment. After combination treatments of STZ and BCNU, the number of SCEs observed in 9L tumors was additive but was synergistic in 9L-2 tumors. O6-alkylguanine DNA alkyltransferase activity (AGT) was measured in 9L and 9L-2 cells in vitro. No AGT activity was detected in 9L cells, however, a low level of activity was measured in 9L-2. In vitro, treatment of 9L-2 cells with STZ produced a dose dependent inhibition of AGT activity. We interpret, these results to suggest that STZ pretreatment potentiated the effects of BCNU in 9L-2 tumors by inhibiting AGT activity. The observations in this study suggest that measurement of SCE induction in intracerebral tumor models may provide a useful strategy for evaluating the effectiveness of new agents and potential therapeutic combinations for the treatment of gliomas.

Animals↗
PubMed2000

O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma.

Local delivery of carmustine (BCNU) via biodegradable polymers prolongs survival against experimental brain tumors and in human clinical trials. O6-benzylguanine (O6-BG), a potent inhibitor of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), has been shown to reduce nitrosourea resistance and, thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models. In this report, we demonstrate that O6-BG can potentiate the activity of BCNU delivered intracranially via polymers in rats challenged with a lethal brain tumor. Fischer 344 rats received a lethal intracranial challenge of 100,000 F98 glioma cells (F98 cells have significant AGT activity, 328 fmol/mg protein). Five days later, animals receiving an i.p. injection of O6-BG (50 mg/kg) 2 h prior to BCNU polymer (3.8% BCNU by weight) implantation had significantly improved survival (n = 7; median survival, 34 days) over animals receiving either O6-BG alone (n = 7; median survival, 22 days; P = 0.0002) or BCNU polymer alone (n = 8; median survival, 25 days; P = 0.0001). Median survival for the control group (n = 8) was 23.5 days. Moreover, there was no physical, behavioral, or pathological evidence of treatment-related toxicity. These findings suggest that O6-BG can potentiate the effects of interstitially delivered BCNU and, for tumors expressing significant AGT, may be necessary for the BCNU to provide a meaningful therapeutic benefit. Given the clinical use of BCNU polymers against malignant gliomas, concurrent treatment with O6-BG may provide an important addition to our therapeutic armamentarium.

Animals↗
PubMed2001

Intraarterial delivery of genetic vectors for the treatment of malignant brain tumors.

BACKGROUND: The transfer of therapeutic genes into malignant brain tumors has been the subject of intense preclinical and clinical research in recent years. Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothelial cells participate in a variety of physiological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer. OBJECTIVE: To assess the anti-tumor effect of transferring a drug-susceptibility gene into endothelial cells of the tumor vasculature. METHODS: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this approach, without and with subsequent treatment with a pro-drug (ganciclovir), was evaluated. RESULTS: No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain. CONCLUSION: The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.

Animals↗
PubMed2002

Tumor immunity within the central nervous system stimulated by recombinant Listeria monocytogenes vaccination.

Tumors arising within the central nervous system (CNS) present the immune system with a challenging target, given the heterogeneous nature of these neoplasms and their location within an "immunologically privileged" site. We used the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a pseudotumor antigen to investigate recombinant Listeria monocytogenes as a tumor vaccine against s.c. and intracerebral challenges with a NP-expressing glioma, 9L-NP. Using Fischer 344 rats, we demonstrate that vaccination with recombinant L. monocytogenes-NP stimulates protection against s.c., but not intracerebral, 9L-NP tumor challenge in an antigen-specific, CD8(+) T-cell-dependent manner. After s.c. tumor rejection, enhanced antitumor immunity is achieved via epitope spreading that permits complete resistance against lethal intracerebral challenge with 9L-NP and with the untransfected parental 9L tumor. Unlike the CD8(+)-dependent immune responses against s.c. 9L-NP tumors, this expanded intracerebral immunity against endogenous tumor-associated antigens is dependent on both CD4(+) and CD8(+) T cells. Taken together, these results demonstrate that the mechanisms of tumor immunity within the brain are different from those elicited against non-CNS tumors. Furthermore, vaccination approaches exploiting the concept of epitope spreading may enhance the efficacy of antitumor immune responses within the immunologically privileged CNS, potentially mediating tumor cell killing through both CD4(+)- and CD8(+)-dependent effector pathways.

Animals↗