Tumor-bearing Brain Research Articles

The impact of bevacizumab on temozolomide concentrations in intracranial U87 gliomas

An important question in the sequencing of anti-cancer therapies in patients with glioblastoma (GBM) is whether concurrent anti-angiogenesis therapies improve or impair brain concentrations of concomitantly administered cytotoxic therapies. The purpose of this study is to assess the intratumoral disposition of temozolomide (TMZ) via microdialysis before and after bevacizumab in an intracranial GBM xenograft model. Microdialysis probes were placed within tumor and contralateral brain in athymic rats bearing U87 intracerebral gliomas. TMZ (50 mg/kg oral) was administered 10 days thereafter. Extracellular fluid (ECF) was collected for 6 h. BEV was administered (10 mg/kg IV), and TMZ was re-dosed (50 mg/kg oral) 36 h thereafter with additional ECF collection. All ECF samples were assessed for TMZ concentration with liquid chromatography-tandem mass spectrometry. Tumor TMZ mean area under the concentration-time curve (AUC(0-∞)) was 3.35 μg h/mL pre-BEV. Post-BEV, tumor mean TMZ AUC(0-∞) was 3.98 μg h/mL. In non-tumor brain, mean TMZ AUC(0-∞) pre-BEV was 3.22 μg h/mL and post-BEV was 3.34 μg h/mL. There were no statistically significant changes in TMZ pharmacokinetics before or after BEV in the athymic rat U87 intracranial glioma model. BEV and TMZ are being investigated as a combination therapy in several ongoing studies for patients with glioma. These data reassuringly suggest that BEV does not significantly change the ECF tumor concentrations of TMZ in either tumor-bearing or normal brain when dosed 36 h prior to TMZ.

Multiscale Modeling for Image Analysis of Brain Tumor Studies

Image-based modeling of tumor growth combines methods from cancer simulation and medical imaging. In this context, we present a novel approach to adapt a healthy brain atlas to MR images of tumor patients. In order to establish correspondence between a healthy atlas and a pathologic patient image, tumor growth modeling in combination with registration algorithms is employed. In a first step, the tumor is grown in the atlas based on a new multiscale, multiphysics model including growth simulation from the cellular level up to the biomechanical level, accounting for cell proliferation and tissue deformations. Large-scale deformations are handled with an Eulerian approach for finite element computations, which can operate directly on the image voxel mesh. Subsequently, dense correspondence between the modified atlas and patient image is established using nonrigid registration. The method offers opportunities in atlas-based segmentation of tumor-bearing brain images as well as for improved patient-specific simulation and prognosis of tumor progression.

Enhanced anti-glioblastoma efficacy by PTX-loaded PEGylated poly(ɛ-caprolactone) nanoparticles: In vitro and in vivo evaluation

The aim of this work was to investigate the anti-tumor effect of paclitaxel (PTX)-loaded methoxy poly(ethylene glycol)-poly(ɛ-caprolactone) nanoparticles (MPEG-NP/PTX) against glioblastoma multiforme (GBM). MPEG-NP/PTX was prepared by the emulsion and evaporation technique with particle size of 72.5 ± 2.2 nm and did not change remarkably during the period of 21-day storage at 4 °C. The drug-loading coefficient and encapsulation ratio of optimized formulation were 8.2 ± 0.6% and 90.4 ± 2.3%, respectively. The in vitro release behavior exhibits a biphase release manner and was affected by PEG segment. In vitro cytotoxicity was assessed using C6 cell lines and was compared to Taxol and PTX-loaded poly(ɛ-caprolactone) conventional nanoparticles (NP/PTX). Cell viability assay against C6 cells exhibited higher or at least comparable cytotoxicity than that of Taxol and NP/PTX. More importantly, in vivo real-time fluorescence imaging analysis in intracranial C6 glioblastoma bearing mice showed that the methoxy poly(ethylene glycol)-poly(ɛ-caprolactone) nanoparticles (MPEG-NP) displayed much stronger fluorescence signal and 3-fold larger Area-Under-Curve (AUC) than poly(ɛ-caprolactone) conventional nanoparticles (NP) in tumor-bearing brain. Furthermore, in vivo anti-glioblastoma effect exhibited the mean survive time of MPEG-NP/PTX (28 days) was much longer than those of Taxol injection (20 days) and NP/PTX (23 days). Therefore, MPEGylated poly(ɛ-caprolactone) nanoparticles significantly enhanced the anti-glioblastoma activity of PTX and might be considered a promising drug delivery system against advanced glioblastoma.

Brain–Tumor Interaction Biophysical Models for Medical Image Registration

State-of-the art algorithms for deformable image registration are based on the minimization of an image similarity functional that is regularized by adding a penalty term on the deformation map. The penalty function typically represents a smoothness regularization. In this article, we use a constrained optimization formulation in which the image similarity functional is coupled to a biophysical model. This formulation is pertinent when the data have been generated by imaging tissue that undergoes deformations due to an actual biophysical phenomenon. Such is the case of coregistering tumor-bearing brain images from the same individual. We present an approximate model that couples tumor growth with the mechanical deformations of the surrounding brain tissue. We consider primary brain tumors—in particular, gliomas. Glioma growth is modeled by a reaction-advection-diffusion PDE, with a two-way coupling with the underlying tissue elastic deformation. Tumor bulk, infiltration, and subsequent mass effects are not regarded separately but are captured by the model itself in the course of its evolution. Our formulation allows for updating the tumor diffusion coefficient following structural displacements caused by tumor growth/infiltration. Our forward problem implementation builds on the PETSc library of Argonne National Laboratory. Our reformulation results in a very small parameter space, and we use the derivative-free optimization library APPSPACK of Sandia National Laboratories. We test the forward model and the optimization framework by using landmark-based similarity functions and by applying it to brain tumor data from clinical and animal studies. State-of-the-art registration algorithms fail in such problems due to excessive deformations. We compare our results with previous work in our group, and we observed up to 50% improvement in landmark deformation prediction. We present preliminary validation results in which we were able to reconstruct deformation fields using four degrees of freedom. Our study demonstrates the validity of our formulation and points to the need for richer datasets and fast optimization algorithms.

Survival of transplanted neural progenitor cells enhanced by brain irradiation

Authors of previous studies have reported that adult transplanted neural progenitor cells (NPCs) are suitable for brain cell replacement or gene delivery. In this study, the authors evaluated survival and integration of adult rat-derived NPCs after transplantation and explored the potential impact on transplant survival of various mechanical and biological factors of clinical importance. Adult female Fischer 344 rats were used both as a source and recipient of transplanted NPCs. Both 9L and RG2 rat glioma cells were used to generate in vivo brain tumor models. On the 5th day after tumor implantation, NPCs expressing green fluorescent protein (GFP) were administered either intravenously (3.5 x 10(7) cells) or by stereotactic injection (1 x 10(4)-1 x 10(6) cells) into normal or tumor-bearing brain. The authors evaluated the effect of delivery method (sharp compared with blunt needles, normal compared with zero-volume needles, phosphate-buffered saline compared with medium as vehicle), delivery sites (intravenous compared with intratumoral compared with intraparenchymal), and pretreatment with an immunosuppressive agent (cyclosporin) or brain irradiation (20-40 Gy) on survival and integration of transplanted NPCs. Very few cells survived when less than 10(5) cells were transplanted. When 10(5) cells or more were transplanted, only previously administered brain irradiation significantly affected survival and integration of NPCs. Although GFP-containing NPCs could be readily detected 1 day after injection, few cells survived 4 days to 1 week unless preceded by whole-brain radiation (20 or 40 Gy in a single fraction), which increased the number of GFP-containing NPCs within the tissue more than fivefold. The authors' findings indicate that most NPCs, including those from a syngeneic autologous source, do not survive at the site of implantation, but that brain irradiation can facilitate subsequent survival in both normal and tumor-bearing brain. An understanding of the mechanisms of this effect could lead to improved survival and clinical utility of transplanted NPCs.

In Vitro and in Vivo Imaging Studies of a New Endohedral Metallofullerene Nanoparticle

To evaluate the effectiveness of a functionalized trimetallic nitride endohedral metallofullerene nanoparticle as a magnetic resonance (MR) imaging proton relaxation agent and to follow its distribution for in vitro agarose gel infusions and in vivo infusions in rat brain. The animal study was approved by the animal care and use committee. Gd(3)N@C(80) was functionalized with poly(ethylene glycol) units, and the carbon cage was hydroxylated to provide improved water solubility and biodistribution. Relaxation rate measurements (R1 = 1/T1 and R2 = 1/T2) of water solutions of this contrast agent were conducted at 0.35-, 2.4-, and 9.4-T MR imaging. Images of contrast agent distributions were produced following infusions in six agarose gel samples at 2.4 T and from direct brain infusions into normal and tumor-bearing rat brain at 2.4 T. The relaxivity of a control functionalized lutetium agent, Lu(3)N@C(80), was also determined. Water hydrogen MR imaging relaxivity (r1) for this metallofullerene nanoparticle was markedly higher than that for commercial agents (eg, gadodiamide); r1 values of 102, 143, and 32 L . mmol(-1) . sec(-1) were measured at 0.35, 2.4, and 9.4 T, respectively. In studies of in vitro agarose gel infusion, the use of functionalized Gd(3)N@C(80) at concentrations an order of magnitude lower resulted in equivalent visualization in comparison with commercial agents. Comparable contrast enhancement was obtained with direct infusions of 0.013 mmol/L of Gd(3)N@C(80) and 0.50 mmol/L of gadodiamide in live normal rat brain. Elapsed-time studies demonstrated lower diffusion rates for Gd(3)N@C(80) relative to gadodiamide in live normal rat brain tissue. Functionalized metallofullerenes directly infused into a tumor-bearing brain provided an improved tumor delineation in comparison with the intravenously injected conventional Gd(3+) chelate. A control lutetium functionalized Lu(3)N@C(80) nanoparticle exhibited very low MR imaging relaxivity. The new functionalized trimetallic nitride endohedral metallofullerene species Gd(3)N@C(80)[DiPEG5000(OH)(x)] is an effective proton relaxation agent, as demonstrated with in vitro relaxivity and MR imaging studies, in infusion experiments with agarose gel and in vivo rat brain studies simulating clinical conditions of direct intraparenchymal drug delivery for the treatment of brain tumors.

A Quantitative Model of Tumor-induced Angiogenesis in the Nude Mouse

Novel animal models allowing for the quantification of tumor-induced angiogenesis and cell migration may offer significant insight into the characterization and multidisciplinary treatment of brain tumors. In this study, we seek to establish such a model in tumor-bearing brain, allowing for a clear demarcation of primary and satellite tumor tissue in conjunction with precise quantification of cerebral microvasculature. We used green fluorescent protein-transfected 9L-gliosarcoma cells stereotactically injected into the brain parenchyma of nude mice perfused with tetramethylrhodamine-dextran immediately before they were killed. New three-dimensional analytical software developed in our laboratory provided a quantitative analysis of laser-scanning confocal microscopy images of dextran-labeled cerebral microvessels. Our data confirm significant angiogenesis in tumor and brain adjacent to tumor. Because these highly infiltrative malignant brain tumors interdigitate with normal brain parenchyma through finger-like projections at the periphery of the solid tumor boundary, therapeutic options targeting tumor blood flow--combined with novel three-dimensional imaging to localize and track such interventions--may offer new hope for glioma management. To our knowledge, this system represents the first animal brain tumor model allowing for the precise colocalization and quantification of angiogenesis and tumor cell invasion, which may play an important role in the development of future therapy for brain tumors.

The use of intracerebral microdialysis for the determination of pharmacokinetic profiles of anticancer drugs in tumor-bearing rat brain.

The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated. Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX. MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250%). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65%). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain. Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.

Methionine sulfoximine intensifies cancer anorexia

Consistent anorexia was first observed 33 days after inoculating Fischer 344 rats with methylcholanthrene-induced sarcoma. Daily treatment of a similar group of rats with the glutamine synthetase inhibitor, methionine sulfoximine, elicited significant reductions of feeding by day 29 at a dose that had no effect on nontumor-bearing rats. Blood concentrations of ammonia were elevated in both groups of tumor-bearing rats and brain ammonia level was increased in the methionine sulfoximine-treated tumor-bearing rats. Forebrain concentrations of tyrosine, tryptophan, DOPAC and 5-HIAA were elevated in both groups of tumor-bearing rats. Since ammonia is detoxified through the glutamine synthetase reaction, these results suggest that blood and brain ammonia concentrations are more important than the neurochemical consequences of ammonia detoxification for the etiology of cancer anorexia.

Distribution of 10B after infusion of Na210B12H11SH into a patient with malignant astrocytoma

If a sufficient concentration of the stable isotope 10B is introduced into a neoplasm, radiation therapy can be effected by short-range heavy charged particles from the disintegration of 10B by slow neutrons. Brain tumors were irradiated postoperatively by Hatanaka and co-workers in Japan using a 1 to 2 hour intraarterial infusion of 10B-enriched Na2B12H11SH (Na210B12H11SH) before exposure of the tumor-bearing area of the brain to slow neutrons from a 100 kilowatt nuclear reactor. The clinical outcome of such boron neutron capture therapy has been favorably impressive in some patients, but its efficacy in brain tumors needs improvement. In our study, a terminally ill patient with malignant astrocytoma was infused intravenously with Na210B12H11SH for 25 hours. The postmortem distribution of 10B in unfixed, frozen, tumor-bearing brain and spinal cord tissues was studied by comparing representative cryostat sections of these specimens with neutron-induced heavy charged particle radiographs of the same sections. Preferential accumulation of 10B was observed in the tumor, with relatively little accumulation of 10B in the parenchyma of the central nervous system. (Neurosurgery 24:6-11, 1989)

Distribution of 10B after infusion of Na210B12H11SH into a patient with malignant astrocytoma: implications for boron neutron capture therapy.

If a sufficient concentration of the stable isotope 10B is introduced into a neoplasm, radiation therapy can be effected by short-range heavy charged particles from the disintegration of 10B by slow neutrons. Brain tumors were irradiated postoperatively by Hatanaka and co-workers in Japan using a 1 to 2 hour intraarterial infusion of 10B-enriched Na2B12H11SH (Na210B12H11SH) before exposure of the tumor-bearing area of the brain to slow neutrons from a 100 kilowatt nuclear reactor. The clinical outcome of such boron neutron capture therapy has been favorably impressive in some patients, but its efficacy in brain tumors needs improvement. In our study, a terminally ill patient with malignant astrocytoma was infused intravenously with Na210B12H11SH for 25 hours. The postmortem distribution of 10B in unfixed, frozen, tumor-bearing brain and spinal cord tissues was studied by comparing representative cryostat sections of these specimens with neutron-induced heavy charged particle radiographs of the same sections. Preferential accumulation of 10B was observed in the tumor, with relatively little accumulation of 10B in the parenchyma of the central nervous system.

Dianhydrogalactitol (NSC-132313): pharmacokinetics in normal and tumor-bearing rat brain and antitumor activity against three intracerebral rodent tumors.

Dianhydrogalactitol (DAG; NSC-132313), a hexitol epoxide, was used to treat intracerebral rodent tumors. DAG was most active against the murine ependymoblastoma [treated/controls (T/C)greater than 440%], less active against murine glioma 26 (T/C approximately 112-150%), and least active against rat 9L gliosarcoma (T/C approximately 100%). Application of a two-compartment open model for plasma disappearance of 14C-DAG in rats gave a volume of distribution at steady state of approximately 872 ml, a clearance of approximately 9.4 ml/minute, and an elimination constant of 0.025/minute. Entry of 14C-DAG was more rapid into the 9L tumor than into the normal brain. When a two-compartment series model for brain and tumor entry was applied, the t1/2 (half-time) for compartmental equilibrium was approximately 22 and 105 minutes in the brain, and 4 and 56 minutes in the 9L tumor. The drug rapidly entered the brain and tumor intracellular compartments. Binding to RNA was linear with time, and the absolute amount of binding was approximately six times greater for RNA than for DNA.